Dicarboxamide derivatives

ABSTRACT

The invention is concerned with novel dicarboxamide derivatives of formula (I) 
     
       
         
         
             
             
         
       
     
     wherein A, B, R c , D and E are as defined in the description and in the claims, as well as physiologically acceptable salts thereof. These compounds inhibit the coagulation factor Xa and can be used as medicaments.

PRIORITY TO RELATED APPLICATIONS

This application is a division of U.S. application Ser. No. 11/263,497,filed Oct. 31, 2005 which claims the benefit of European Application No.04105465.1, filed Nov. 3, 2004 and European Application No. 05100132.9,filed Jan. 12, 2005. The entire contents of the above-identifiedapplications are hereby incorporated by reference.

SUMMARY OF THE INVENTION

The invention is concerned with novel dicarboxamide derivatives of theformula (I)

wherein

A is —CONH— or —NHCO—;

B is optionally substituted phenyl, optionally substituted heteroaryl oroptionally substituted heterocyclyl;R^(c) is optionally substituted aryl, optionally substituted heteroarylor optionally substituted heterocyclyl, one or two carbon atoms of saidaryl, heteroaryl or heterocyclyl ring optionally being replaced with acarbonyl group;D is aryl optionally substituted by one, two or three halogen atomsindependently selected from chlorine, fluorine and bromine or heteroaryloptionally substituted by one, two or three halogen atoms independentlyselected from chlorine, fluorine and bromine;

E is E-1:

E-2:

or E-3:

R¹ and R² are independently from each other hydrogen, halogen, C₁₋₆alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₆ alkyl, amino,mono-substituted amino, di-substituted amino, hydroxy, C₁₋₆ alkoxy,mono-substituted amino-C₁₋₆ alkyl, di-substituted amino-C₁₋₆ alkyl,hydroxyl C₁₋₆ alkyl orR¹ and R² together form ═O or

orR¹ and R² are bonded to each other to form optionally substitutedheterocyclyl, together with the carbon atom to which R¹ and R² areattached;R³ and R⁴ are independently from each other hydrogen, C₁₋₆ alkyl,carboxyl, C₁₋₆ alkoxycarbonyl, carbamoyl, mono- or di-substitutedamino-carbonyl, optionally substituted aryl carbonyl, optionallysubstituted heterocyclylcarbonyl, optionally substitutedheteroarylcarbonyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, hydroxyl C₁₋₆ alkyl,halo C₁₋₆ alkyl, cyano C₁₋₆ alkyl, C₁₋₆ alkoxy C₁₋₆ alkyl, amino C₁₋₆alkyl, mono- or di-substituted amino-C₁₋₆ alkyl, optionally substitutedaryl C₁₋₆ alkyl, optionally substituted heterocyclyl C₁₋₆ alkyl,optionally substituted heteroaryl C₁₋₆ alkyl, optionally substitutedaryl C₁₋₆ alkoxy C₁₋₆ alkyl, optionally substituted heteroaryl C₁₋₆alkoxy C₁₋₆ alkyl, optionally substituted heterocyclyl C₁₋₆ alkoxy C₁₋₆alkyl orR³ and R⁴ are bonded to each other to form C₃₋₇ cycloalkyl, togetherwith the carbon atom to which R³ and R⁴ are attached;R⁵ and R⁶ are independently from each other hydrogen, C₁₋₆ alkyl, cyano,C₁₋₆ alkoxycarbonyl, C₂₋₆ alkenyloxycarbonyl, C₂₋₆ alkynyloxycarbonyl,hydroxyl C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, carboxyl, mono- or di-C₁₋₆alkyl substituted amino-carbonyl, aminocarbonyl, optionally substitutedheterocyclyl carbonyl, optionally substituted heteroaryl carbonyl oroptionally substituted aryl carbonyl;R⁷, R⁸, R⁹ and R¹⁰ are independently from each other hydrogen, C₁₋₆alkyl or hydroxy;R¹¹ and R¹² are independently from each other hydrogen, C₁₋₆ alkyl orC₂₋₆ alkenyl;and pharmaceutically acceptable salts thereof.

Further, the invention is concerned with a process for the manufactureof the above compounds, pharmaceutical preparations which contain suchcompounds as well as the use of these compounds for the production ofpharmaceutical preparations.

The compounds of formula (I) are compounds that inhibit the activity ofcoagulation factor Xa. These compounds consequently influence bloodcoagulation. They therefore inhibit the formation of thrombi and can beused for the treatment and/or prevention of thrombotic disorders, suchas amongst others, arterial and venous thrombosis, deep vein thrombosis,peripheral arterial occlusive disease (PAOD), unstable angina pectoris,myocardial infarction, coronary artery disease, pulmonary embolism,stroke (cerebral thrombosis) due to atrial fibrillation, inflammationand arteriosclerosis. They can also be used in the treatment of acutevessel closure associated with thrombolytic therapy and restenosis, e.g.after transluminal coronary angioplasty (PTCA) or bypass grafting of thecoronary or peripheral arteries and in the maintenance of vascularaccess patency in long term hemodialysis patients. Factor Xa inhibitorsof this invention may form part of a combination therapy with ananticoagulant with a different mode of action or with a plateletaggregation inhibitor or with a thrombolytic agent. Furthermore, thesecompounds have an effect on tumor cells and prevent metastases. They cantherefore also be used as antitumor agents.

Other inhibitors of factor Xa, which are not structurally related to thecompounds of the present invention, had previously been suggested forthe inhibition of the formation of thrombi and for the treatment ofrelated diseases (WO 03/045912). However, there is still a need fornovel factor Xa inhibitors which exhibit improved pharmacologicalproperties, e.g. an improved selectivity towards coagulation factor Xa.

The present invention provides the novel compounds of formula (I) whichare factor Xa inhibitors, intermediates for the synthesis of compoundsof formula (I), and methods of using compounds of formula (I). Thecompounds of the present invention unexpectedly inhibit coagulationfactor Xa and also exhibit improved pharmacological properties comparedto other compounds already known in the art.

DETAILED DESCRIPTION OF THE INVENTION

All patents, patent applications, and publications cited herein areincorporated by reference in their entirety. In the event of a conflictin teachings, the present disclosure is controlling.

Definitions

Unless otherwise indicated, the following definitions are set forth toillustrate and define the meaning and scope of the various terms used todescribe the invention herein.

The term “halogen” or “halo” means fluorine, chlorine, bromine andiodine, with fluorine, chlorine and bromine being preferred.

The term “C₁₋₆ alkyl”, alone or in combination with other groups, meansa branched or straight-chain monovalent alkyl radical, having one to sixcarbon atoms. This term is further exemplified by such radicals asmethyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl. C₁₋₄alkyl is more preferred.

The term “C₂₋₆ alkynyl”, alone or in combination with other groups,means a straight-chain or branched hydrocarbon residue comprising atripple bond and 2 to 6 carbon atoms, such as e.g. 2-propinyl.

The term “halo C₁₋₆ alkyl” means C₁₋₆ alkyl substituted by one or moresame or different halogen atoms independently selected from the groupconsisting of chlorine, fluorine and bromine.

The term “cyano C₁₋₆ alkyl” means C₁₋₆ alkyl substituted by one or morecyano groups, preferably one cyano group.

The term “hydroxy C₁₋₆ alkyl” means C₁₋₆ alkyl substituted by one ormore hydroxy groups, preferably one or two hydroxy groups.

The term “C₃₋₇ cycloalkyl”, alone or in combination with other groups,means a saturated monovalent cyclic hydrocarbon radical of three toseven ring carbons, e.g., cyclopropyl, cyclobutyl, cyclohexyl.

The term “C₁₋₆ alkoxy”, alone or in combination with other groups, meansthe group R′—O—, wherein R′ is a C₁₋₆ alkyl.

The term “C₂₋₆ alkenyl”, alone or in combination with other groups,means a straight-chain or branched hydrocarbon residue comprising anolefinic bond, having two to six carbon atoms, such as e.g. ethenyl,2-propenyl.

The term “aryl”, alone or in combination with other groups, means aphenyl or a naphthyl group, preferably a phenyl group. The term“optionally substituted aryl” means an aryl group described above, whichis optionally substituted by one to five, preferably one to threesubstituents independently selected from the group consisting ofhalogen, hydroxy, C₁₋₆ alkyl, halo C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylsulfonyl, C₁₋₆ alkyl sulfinyl, C₁₋₆ alkylthio, amino, amino C₁₋₆ alkyl,mono- or di-substituted amino-C₁₋₆ alkyl, nitro, cyano, acyl, carbamoyl,mono- or di-substituted amino, aminocarbonyl, mono- or di-substitutedamino-carbonyl, aminocarbonyl C₁₋₆ alkoxy, mono- or di-substitutedamino-carbonyl-C₁₋₆ alkoxy, hydroxy-C₁₋₆ alkyl, carboxyl, C₁₋₆ alkoxycarbonyl, aryl C₁₋₆ alkoxy, heteroaryl C₁₋₆ alkoxy, heterocyclyl C₁₋₆alkoxy, C₁₋₆ alkoxycarbonyl C₁₋₆ alkoxy, carbamoyl C₁₋₆ alkoxy andcarboxyl C₁₋₆ alkoxy, preferably selected from the group consisting ofhalogen, hydroxy, C₁₋₆ alkyl, halo C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylsulfonyl, C₁₋₆ alkyl sulfinyl, C₁₋₆ alkylthio, amino, mono-C₁₋₆ alkylsubstituted amino, di-C₁₋₆ alkyl substituted amino, amino C₁₋₆ alkyl,mono-C₁₋₆ alkyl substituted amino-C₁₋₆ alkyl, di-C₁₋₆ alkyl substitutedamino-C₁₋₆ alkyl, nitro and cyano.

The term “heterocyclyl”, alone or combination with other groups, meansnon-aromatic monocyclic radicals of three to eight ring atoms in whichone or two ring atoms are heteroatoms selected from N, O, or S(O)_(n)(where n is an integer from 0 to 2), the remaining ring atoms being C.One or two ring carbon atoms of heterocyclyl group may be replaced witha carbonyl group.

The term “optionally substituted heterocyclyl” means a heterocyclylgroup described above, which is optionally substituted independently byone, two, or three substituents, preferably one or two substituentsselected from the group consisting of halogen, hydroxy, C₁₋₆ alkyl, haloC₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkyl sulfonyl, C₁₋₆ alkyl sulfinyl, C₁₋₆alkylthio, amino, amino C₁₋₆ alkyl, mono- or di-substituted amino-C₁₋₆alkyl, nitro, cyano, acyl, carbamoyl, mono- or di-substituted amino,aminocarbonyl, mono- or di-substituted amino-carbonyl, aminocarbonylC₁₋₆ alkoxy, mono- or di-substituted amino-carbonyl-C₁₋₆ alkoxy,hydroxy-C₁₋₆ alkyl, carboxyl, C₁₋₆ alkoxy carbonyl, aryl C₁₋₆ alkoxy,heteroaryl C₁₋₆ alkoxy, heterocyclyl C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonylC₁₋₆ alkoxy, carbamoyl C₁₋₆ alkoxy and carboxyl C₁₋₆ alkoxy, preferablyselected from the group consisting of halogen, hydroxy, C₁₋₆ alkyl, haloC₁₋₆ alkyl, C₁₋₆ alkoxy, acyl, C₁₋₆ alkyl sulfonyl, C₁₋₆ alkyl sulfinyl,C₁₋₆ alkylthio, amino, mono-C₁₋₆ alkyl substituted amino, di-C₁₋₆ alkylsubstituted amino, amino C₁₋₆ alkyl, mono-C₁₋₆ alkyl substitutedamino-C₁₋₆ alkyl, di-C₁₋₆ alkyl substituted amino-C₁₋₆ alkyl, nitro,carbamoyl, mono- or di-substituted amino-carbonyl, hydroxy-C₁₋₆ alkyl,carboxyl, C₁₋₆ alkoxy carbonyl and cyano, more preferably selected fromthe group consisting of halogen, hydroxy, C₁₋₆ alkyl, halo C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ alkyl sulfonyl, C₁₋₆ alkyl sulfinyl, C₁₋₆ alkylthio,amino, mono-C₁₋₆ alkyl substituted amino, di-C₁₋₆ alkyl substitutedamino, amino C₁₋₆ alkyl, mono-C₁₋₆ alkyl substituted amino-C₁₋₆ alkyl,di-C₁₋₆ alkyl substituted amino-C₁₋₆ alkyl, nitro and cyano.

The term “heteroaryl”, alone or combination with other groups, means amonocyclic or bicyclic radical of 5 to 12 ring atoms having at least onearomatic ring containing one, two, or three ring heteroatoms selectedfrom N, O, and S, the remaining ring atoms being C, with theunderstanding that the attachment point of the heteroaryl radical willbe on an aromatic ring. One or two ring carbon atoms of heteroaryl groupmay be replaced with a carbonyl group. The term “optionally substitutedheteroaryl” means a heteroaryl group described above, which isoptionally substituted independently with one, two, or threesubstituents, preferably one or two substituents selected from the groupconsisting of halogen, hydroxy, C₁₋₆ alkyl, halo C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ alkyl sulfonyl, C₁₋₆ alkyl sulfinyl, C₁₋₆ alkylthio, amino,amino C₁₋₆ alkyl, mono- or di-substituted amino-C₁₋₆ alkyl, nitro,cyano, acyl, carbamoyl, mono- or di-substituted amino, aminocarbonyl,mono- or di-substituted amino-carbonyl, aminocarbonyl C₁₋₆ alkoxy, mono-or di-substituted amino-carbonyl-C₁₋₆ alkoxy, hydroxy-C₁₋₆ alkyl,carboxyl, C₁₋₆ alkoxy carbonyl, aryl C₁₋₆ alkoxy, heteroaryl C₁₋₆alkoxy, heterocyclyl C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl C₁₋₆ alkoxy,carbamoyl C₁₋₆ alkoxy and carboxyl C₁₋₆ alkoxy, preferably selected fromthe group consisting of halogen, hydroxy, C₁₋₆ alkyl, halo C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ alkyl sulfonyl, C₁₋₆ alkyl sulfinyl, C₁₋₆ alkylthio,amino, mono-C₁₋₆ alkyl substituted amino, di-C₁₋₆ alkyl substitutedamino, amino C₁₋₆ alkyl, mono-C₁₋₆ alkyl substituted amino-C₁₋₆ alkyl,di-C₁₋₆ alkyl substituted amino-C₁₋₆ alkyl, nitro, carbamoyl, mono- ordi-substituted amino-carbonyl, hydroxy-C₁₋₆ alkyl, carboxyl, C₁₋₆ alkoxycarbonyl and cyano.

The term “optionally substituted phenyl” means a phenyl group optionallysubstituted by one to five substituents, preferably one to threesubstituents independently selected from the group consisting ofhalogen, hydroxy, C₁₋₆ alkyl, halo C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylsulfonyl, C₁₋₆ alkyl sulfinyl, C₁₋₆ alkylthio, amino, amino C₁₋₆ alkyl,mono- or di-substituted amino-C₁₋₆ alkyl, nitro, cyano, acyl, carbamoyl,mono- or di-substituted amino, aminocarbonyl, mono- or di-substitutedamino-carbonyl, aminocarbonyl C₁₋₆ alkoxy, mono- or di-substitutedamino-carbonyl-C₁₋₆ alkoxy, hydroxy-C₁₋₆ alkyl, carboxyl, C₁₋₆ alkoxycarbonyl, aryl C₁₋₆ alkoxy, heteroaryl C₁₋₆ alkoxy, heterocyclyl C₁₋₆alkoxy, C₁₋₆ alkoxycarbonyl C₁₋₆ alkoxy, carbamoyl C₁₋₆ alkoxy andcarboxyl C₁₋₆ alkoxy, preferably selected from the group consisting ofhalogen, hydroxy, C₁₋₆ alkyl, halo C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylsulfonyl, C₁₋₆ alkyl sulfinyl, C₁₋₆ alkylthio, amino, mono-C₁₋₆ alkylsubstituted amino, di-C₁₋₆ alkyl substituted amino, amino C₁₋₆ alkyl,mono-C₁₋₆ alkyl substituted amino-C₁₋₆ alkyl, di-C₁₋₆ alkyl substitutedamino-C₁₋₆ alkyl, nitro and cyano.

The term “mono-substituted amino” and “di-substituted amino”, alone orcombination with other groups, mean —NHR and —NRR′ respectively, inwhich R and R′ are independently selected from the group consisting ofhydroxy, C₁₋₆ alkyl, hydroxy C₁₋₆ alkyl, C₁₋₆ alkoxy C₁₋₆ alkyl,carbamoyl C₁₋₆ alkyl, halo C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkyl sulfonyl, C₁₋₆ alkyl sulfinyl, C₁₋₆alkylthio, mono- or di-C₁₋₆ alkyl substituted amino-sulfonyl, mono- ordi-C₁₋₆ alkyl substituted amino-sulfinyl, mono- or di-C₁₋₆ alkylsubstituted amino-thio, mono- or di-C₁₋₆ alkyl substituted amino-C₁₋₆alkyl, mono- or di-C₁₋₆ alkyl substituted aminocarbonyl-C₁₋₆ alkyl,acyl, halo C₁₋₆ alkylcarbonyl and C₁₋₆ alkoxycarbonyl, preferablyselected from the group consisting of hydroxy, C₁₋₆ alkyl, hydroxy C₁₋₆alkyl, C₁₋₆ alkoxy C₁₋₆ alkyl, carbamoyl C₁₋₆ alkyl, halo C₁₋₆ alkyl,C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylsulfonyl, C₁₋₆ alkyl sulfinyl, C₁₋₆ alkylthio, mono- or di-C₁₋₆ alkylsubstituted amino-sulfonyl, mono- or di-C₁₋₆ alkyl substitutedamino-sulfinyl, mono- or di-C₁₋₆ alkyl substituted amino-thio, mono- ordi-C₁₋₆ alkyl substituted amino-C₁₋₆ alkyl, mono- or di-C₁₋₆ alkylsubstituted aminocarbonyl-C₁₋₆ alkyl, acyl and C₁₋₆ alkoxycarbonyl,preferably selected from the group consisting of hydroxy, C₁₋₆ alkyl,hydroxy C₁₋₆ alkyl, halo C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkyl sulfonyl, C₁₋₆ alkyl sulfinyl, C₁₋₆alkylthio, mono- or di-C₁₋₆ alkyl substituted amino-sulfonyl, mono- ordi-C₁₋₆ alkyl substituted amino-sulfinyl, mono- or di-C₁₋₆ alkylsubstituted amino-thio, acyl and C₁₋₆ alkoxycarbonyl.

The term “acyl”, alone or combination with other groups, means —C(═O)R,in which R is H or C₁₋₆ alkyl.

Preferred radicals for the chemical groups whose definitions are givenabove are those specifically exemplified in Examples.

Compounds of formula (I) can form pharmaceutically acceptable acidaddition salts. Examples of such pharmaceutically acceptable salts aresalts of compounds of formula (I) with physiologically compatiblemineral acids, such as hydrochloric acid, sulphuric acid, sulphurousacid or phosphoric acid; or with organic acids, such as methanesulphonicacid, p-toluenesulphonic acid, acetic acid, lactic acid, trifluoroaceticacid, citric acid, fumaric acid, maleic acid, tartaric acid, succinicacid or salicylic acid. The term “pharmaceutically acceptable salts”refers to such salts. Compounds of formula (I) in which a COOH group ispresent can further form salts with bases. Examples of such salts arealkaline, earth-alkaline and ammonium salts such as e.g. Na—, K—, Ca—and Trimethylammoniumsalt. The term “pharmaceutically acceptable salts”also refers to such salts. Acid addition salts as described above arepreferred.

“Leaving group” has the meaning conventionally associated with it insynthetic organic chemistry, i.e., an atom or a group capable of beingdisplaced by a nucleophile and includes halo (such as chloro, bromo, andiodo), alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (e.g.,acetoxy), arylcarbonyloxy, mesyloxy, tosyloxy,trifluoromethanesulfonyloxy, aryloxy (e.g., 2,4-dinitrophenoxy),methoxy, N,O-dimethylhydroxylamino.

“Enantiomerically pure” means that the enantiomeric excess exceeds 95%.

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “aryl group optionally substitutedwith an alkyl group” means that the alkyl may but need not be present,and the description includes situations where the aryl group issubstituted with an alkyl group and situations where the aryl group isnot substituted with the alkyl group.

“Pharmaceutically acceptable excipient” means an excipient that isuseful in preparing a pharmaceutical composition that is generally safe,non-toxic and neither biologically nor otherwise undesirable, andincludes excipient that is acceptable for veterinary use as well ashuman pharmaceutical use. A “pharmaceutically acceptable excipient” asused in the specification and claims includes both one and more than onesuch excipient.

Compounds that have the same molecular Formula but differ in the natureor sequence of bonding of their atoms or the arrangement of their atomsin space are termed “isomers.” Isomers that differ in the arrangement oftheir atoms in space are termed “stereoisomers”. Stereoisomers that arenot mirror images of one another are termed “diastereomers” and thosethat are non-superimposable mirror images of each other are termed“enantiomers”. When a compound has an asymmetric center, for example, ifa carbon atom is bonded to four different groups, a pair of enantiomersis possible. An enantiomer can be characterized by the absoluteconfiguration of its asymmetric center and is described by the R- andS-sequencing rules of Cahn, Ingold and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture”.

The compounds of formula (I) wherein E is E-1 or E-2 have at least twoasymmetric centers on the adjacent carbon atoms belonging to acyclopentane or cyclopropane ring. Thus, they can therefore exist as adiastereomeric mixture of trans and cis compounds, or as a pure transcompounds or a pure cis compounds. Moreover, each of trans and ciscompounds can exist as an enantiomeric mixture or as optically purecompounds. The compounds of this invention wherein E is E-3 can possessone or more asymmetric centers. Unless indicated otherwise, thedescription or naming of a particular compound in the specification andclaims is intended to include both individual enantiomers and mixtures,racemic or otherwise, thereof. The methods for the determination ofstereochemistry and the separation of stereoisomers are well-known inthe art (see discussion in Chapter 4 of “Advanced Organic Chemistry”,4th edition J. March, John Wiley and Sons, New York, 1992).

Thus, the invention provides novel dicarboxamide derivatives of theformula (I)

wherein

A is —CONH— or —NHCO—;

B is optionally substituted phenyl, optionally substituted heteroaryl oroptionally substituted heterocyclyl;R^(c) is optionally substituted aryl, optionally substituted heteroarylor optionally substituted heterocyclyl, one or two carbon atoms of saidaryl, heteroaryl or heterocyclyl ring optionally being replaced with acarbonyl group;D is aryl optionally substituted by one, two or three halogen atomsindependently selected from chlorine, fluorine and bromine or heteroaryloptionally substituted by one, two or three halogen atoms independentlyselected from chlorine, fluorine and bromine;

E is E-1:

E-2:

or E-3:

R¹ and R² are independently from each other hydrogen, halogen, C₁₋₆alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₆ alkyl, amino,mono-substituted amino, di-substituted amino, hydroxy, C₁₋₆ alkoxy,mono-substituted amino-C₁₋₆ alkyl, di-substituted amino-C₁₋₆ alkyl,hydroxyl C₁₋₆ alkyl orR and R together form ═O or

orR¹ and R² are bonded to each other to form optionally substitutedheterocyclyl, together with the carbon atom to which R¹ and R² areattached;R³ and R⁴ are independently from each other hydrogen, C₁₋₆ alkyl,carboxyl, C₁₋₆ alkoxycarbonyl, carbamoyl, mono- or di-substitutedamino-carbonyl, optionally substituted aryl carbonyl, optionallysubstituted heterocyclylcarbonyl, optionally substitutedheteroarylcarbonyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, hydroxyl C₁₋₆ alkyl,halo C₁₋₆ alkyl, cyano C₁₋₆ alkyl, C₁₋₆ alkoxy C₁₋₆ alkyl, amino C₁₋₆alkyl, mono- or di-substituted amino-C₁₋₆ alkyl, optionally substitutedaryl C₁₋₆ alkyl, optionally substituted heterocyclyl C₁₋₆ alkyl,optionally substituted heteroaryl C₁₋₆ alkyl, optionally substitutedaryl C₁₋₆ alkoxy C₁₋₆ alkyl, optionally substituted heteroaryl C₁₋₆alkoxy C₁₋₆ alkyl, optionally substituted heterocyclyl C₁₋₆ alkoxy C₁₋₆alkyl orR³ and R⁴ are bonded to each other to form C₃₋₇ cycloalkyl, togetherwith the carbon atom to which R³ and R⁴ are attached;R⁵ and R⁶ are independently from each other hydrogen, C₁₋₆ alkyl, cyano,C₁₋₆ alkoxycarbonyl, C₂₋₆ alkenyloxycarbonyl, C₂₋₆ alkynyloxycarbonyl,hydroxyl C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, carboxyl, mono- or di-C₁₋₆alkyl substituted amino-carbonyl, aminocarbonyl, optionally substitutedheterocyclyl carbonyl, optionally substituted heteroaryl carbonyl oroptionally substituted aryl carbonyl;R⁷, R⁸, R⁹ and R¹⁰ are independently from each other hydrogen, C₁₋₆alkyl or hydroxy;R¹¹ and R¹² are independently from each other hydrogen, C₁₋₆ alkyl orC₂₋₆ alkenyl;and pharmaceutically acceptable salts thereof.

Preferably R³ and R⁴ are independently from each other hydrogen, C₁₋₆alkyl, carboxyl, C₁₋₆ alkoxycarbonyl, carbamoyl, mono- or di-substitutedamino-carbonyl, optionally substituted heterocyclylcarbonyl, optionallysubstituted heteroarylcarbonyl, aryl, optionally substituted heteroaryl,optionally substituted heterocyclyl, hydroxyl C₁₋₆ alkyl, C₁₋₆ alkoxyC₁₋₆ alkyl, amino C₁₋₆ alkyl, mono- or di-substituted amino-C₁₋₆ alkyl,optionally substituted heterocyclyl C₁₋₆ alkyl, optionally substitutedheteroaryl C₁₋₆ alkyl or

R³ and R⁴ are bonded to each other to form C₃₋₇ cycloalkyl, togetherwith the carbon atom to which R³ and R⁴ are attached andR⁵ and R⁶ are independently from each other hydrogen or C₁₋₆ alkyl.

More preferably R³ and R⁴ are independently from each other hydrogen,C₁₋₆ alkyl, carboxyl, C₁₋₆ alkoxycarbonyl, mono- or di-substitutedamino-carbonyl, optionally substituted heterocyclylcarbonyl, aryl,optionally substituted heteroaryl, optionally substituted heterocyclyl,hydroxyl C₁₋₆ alkyl, C₁₋₆ alkoxy C₁₋₆ alkyl, amino C₁₋₆ alkyl, mono- ordi-substituted amino-C₁₋₆ alkyl, optionally substituted heterocyclylC₁₋₆ alkyl, optionally substituted heteroaryl C₁₋₆ alkyl or R³ and R⁴are bonded to each other to form C₃₋₇ cycloalkyl, together with thecarbon atom to which R³ and R⁴ are attached.

While the broadest definition of this invention is described before,certain compounds of Formula (I) are preferred.

A preferred compound of the invention is a compound of Formula (I)wherein E is E-1. When E is E-1, D is preferably aryl optionallysubstituted by one halogen atom selected from chlorine and bromine orheteroaryl optionally substituted by one halogen atom selected fromchlorine and bromine. More preferred halogen atom is chlorine. Arylgroup for D is preferably phenyl. Heteroaryl group for D is preferablymonocyclic or bicyclic radical of 5 to 12 ring atoms having at least onearomatic ring containing one or two ring heteroatoms selected from N andS, such as pyrrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,pyrazolyl, imidazolyl, tetrazolyl, thienyl, isothiazolyl, indolyl,isoindolyl, indolizinyl, indazolyl, quinolyl, isoquinolyl, morepreferably pyridyl, thienyl, pyrimidinyl, pyridazinyl or indolyl,especially phenyl or pyridyl.

When E is E-1, D is further more preferably chlorophenyl orchloropyridyl, especially 4-chlorophenyl or 5-chloro-pyridin-2-yl.4-chlorophenyl is especially preferred.

When E is E-1, B is preferably optionally substituted phenyl oroptionally substituted heteroaryl. Heteroaryl group for B is preferablya monocyclic radical of five or six ring atoms having one or two ringnitrogen atoms, such as pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,pyrazolyl, imidazolyl, pyrrolyl, especially pyridyl. B is morepreferably phenyl or pyridyl, especially phenyl, optionally substitutedby one or two halogen atoms selected independently from the groupconsisting of chlorine, fluorine and bromine. Further more preferredgroup for B is a phenyl substituted by one or two fluorine, especiallyone fluorine. 2-fluorophenyl is especially preferred.

When E is E-1, R^(c) is preferably aryl, heteroaryl or heterocyclyl, onecarbon atom of said aryl, heteroaryl or heterocyclyl ring optionallybeing replaced with a carbonyl group, and said aryl, heteroaryl orheterocyclyl ring optionally being substituted by hydroxy, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ alkyl sulfonyl, amino C₁₋₆ alkyl, mono-C₁₋₆ alkylsubstituted amino-C₁₋₆ alkyl or di-C₁₋₆ alkyl substituted amino-C₁₋₆alkyl, more preferably R^(c) is aryl, heteroaryl or heterocyclyl, onecarbon atom of said aryl, heteroaryl or heterocyclyl ring being replacedwith a carbonyl group at ortho position with respect to B, and saidaryl, heteroaryl or heterocyclyl ring optionally being substituted byhydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkyl sulfonyl, amino C₁₋₆ alkyl,mono-C₁₋₆ alkyl substituted amino-C₁₋₆ alkyl or di-C₁₋₆ alkylsubstituted amino-C₁₋₆ alkyl. Aryl group for R^(c) is preferably phenyl.Heteroaryl group for R^(c) is preferably a monocyclic radical of five orsix ring atoms having one or two ring nitrogen atoms, such as pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, pyrrolyl,more preferably pyridyl, imidazolyl, pyrazinyl, especially pyridyl.Heterocyclyl group for R^(c) is preferably pyrrolidinyl, pyrrolinyl,imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl,piperazinyl, morpholinyl, pyranyl, tetrahydropyranyl,4,5-dihydro-oxazolyl, sultamyl or 4,5-dihydro-thiazolyl, more preferablymorpholinyl, piperidyl or sultamyl. Further preferred group for R^(c) is2-oxo-2H-pyridin-1-yl optionally substituted by C₁₋₆ alkyl or C₁₋₆alkoxy, especially 2-oxo-2H-pyridin-1-yl.

Especially preferred —B—R^(c) is2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl.

When E is E-1, preferably R¹ and R² are independently from each otherhydrogen, hydroxy, C₁₋₆ alkoxy, hydroxy C₁₋₆ alkyl or R¹ and R² togetherform ═O or

or R¹ and R² are bonded to each other to form optionally substitutedheterocyclyl, together with the carbon atom to which R¹ and R² areattached. More preferably R¹ and R² are independently from each otherhydrogen, hydroxy, C₁₋₆ alkoxy, hydroxy C₁₋₆ alkyl or R¹ and R² togetherform

in which R¹¹ and R¹² are hydrogen, or R¹ and R² are bonded to each otherto form

together with the carbon atom to which R¹ and R² are attached.Especially R¹ and R² together form

in which R¹¹ and R¹² are hydrogen.

When E is E-1, A is preferably —CONH—.

When E is E-1, the compounds wherein —B—R^(c) is2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl, D is 4-chlorophenyl and A ispreferably —CONH— are especially preferred.

Particularly preferred compounds in this group are:

-   (1S,2S)-4-Methylene-cyclopentane-1,2-dicarboxylic acid    1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1R,2S)-4-Methylene-cyclopentane-1,2-dicarboxylic acid    1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1S,2S,4S)- or    (1S,2S,4R)-4-Hydroxymethyl-4-methoxy-cyclopentane-1,2-dicarboxylic    acid    1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (5S,6S)-Spiro[2.4]heptane-5,6-dicarboxylic acid    (4-chloro-phenyl)-amide[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide,-   (1S,2S,4S)-4-Fluoro-cyclopentane-1,2-dicarboxylic acid    1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1S,2S,4R)-4-Hydroxy-cyclopentane-1,2-dicarboxylic acid    1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1S,2S,4S)-4-Hydroxy-cyclopentane-1,2-dicarboxylic acid    1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.

Other particularly preferred compounds in this group are:

-   (1S,2S,4S)-4-fluoro-cyclopentane-1,2-dicarboxylic acid    1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1S,2S,4R)-4-fluoro-cyclopentane-1,2-dicarboxylic acid    1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1S,2S,4R)-4-fluoro-cyclopentane-1,2-dicarboxylic acid    1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyrazin-1-yl)-phenyl]-amide},-   ((1S,2S,4R)-4-fluoro-cyclopentane-1,2-dicarboxylic acid    1-[(5-chloro-pyridin-2-yl)-amide]2-{[4-(3-oxo-morpholin-4-yl)-phenyl]-amide}),-   (1S,2S,4R)-4-Fluoro-cyclopentane-1,2-dicarboxylic acid    1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(3-oxo-morpholin-4-yl)-phenyl]-amide}.

Another preferred compound of the invention is a compound of Formula (I)wherein E is E-2.

When E is E-2, D is preferably aryl optionally substituted by onehalogen atom selected from chlorine and bromine or heteroaryl optionallysubstituted by one halogen atom selected from chlorine and bromine. Morepreferred halogen atom is chlorine. Aryl group for D is preferablyphenyl. Heteroaryl group for D is preferably monocyclic or bicyclicradical of 5 to 12 ring atoms having at least one aromatic ringcontaining one or two ring heteroatoms selected from N and S, such aspyrrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl,imidazolyl, tetrazolyl, thienyl, isothiazolyl, indolyl, isoindolyl,indolizinyl, indazolyl, quinolyl, isoquinolyl, more preferably pyridyl,thienyl, pyrimidinyl, pyridazinyl or indolyl, especially phenyl orpyridyl.

When E is E-2, D is further more preferably chlorophenyl orchloropyridyl, especially 4-chlorophenyl or 5-chloro-pyridin-2-yl.4-chlorophenyl is especially preferred.

When E is E-2, B is preferably optionally substituted phenyl oroptionally substituted heteroaryl. Heteroaryl group for B is preferablya monocyclic radical of five or six ring atoms having one or two ringnitrogen atoms, such as pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,pyrazolyl, imidazolyl, pyrrolyl, especially pyridyl. B is morepreferably phenyl or pyridyl, especially phenyl, optionally substitutedby one or two halogen atoms selected independently from the groupconsisting of chlorine, fluorine and bromine. Further more preferredgroup for B is a phenyl substituted by one or two fluorine, especiallyone fluorine. 2-fluorophenyl is especially preferred.

When E is E-2, R^(c) is preferably aryl, heteroaryl or heterocyclyl, onecarbon atom of said aryl, heteroaryl or heterocyclyl ring optionallybeing replaced with a carbonyl group, and said aryl, heteroaryl orheterocyclyl ring optionally being substituted by hydroxy, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ alkyl sulfonyl, amino C₁₋₆ alkyl, mono-C₁₋₆ alkylsubstituted amino-C₁₋₆ alkyl, di-C₁₋₆ alkyl substituted amino-C₁₋₆alkyl, aminocarbonyl C₁₋₆ alkoxy, mono- or di-substitutedamino-carbonyl-C₁₋₆ alkoxy, hydroxy-C₁₋₆ alkyl, carboxyl, C₁₋₆ alkoxycarbonyl, aryl C₁₋₆ alkoxy, heteroaryl C₁₋₆ alkoxy, heterocyclyl C₁₋₆alkoxy, C₁₋₆ alkoxycarbonyl C₁₋₆ alkoxy, carbamoyl C₁₋₆ alkoxy orcarboxyl C₁₋₆ alkoxy, preferably said aryl, heteroaryl or heterocyclylring optionally being substituted by hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₆ alkyl sulfonyl, amino C₁₋₆ alkyl, mono-C₁₋₆ alkyl substitutedamino-C₁₋₆ alkyl, di-C₁₋₆ alkyl substituted amino-C₁₋₆ alkyl. Morepreferably R^(c) is aryl, heteroaryl or heterocyclyl, one carbon atom ofsaid aryl, heteroaryl or heterocyclyl ring being replaced with acarbonyl group at ortho position with respect to B, and said aryl,heteroaryl or heterocyclyl ring optionally being substituted by hydroxy,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkyl sulfonyl, amino C₁₋₆ alkyl,mono-C₁₋₆ alkyl substituted amino-C₁₋₆ alkyl or di-C₁₋₆ alkylsubstituted amino-C₁₋₆ alkyl. Aryl group for R^(c) is preferably phenyl.Heteroaryl group for R^(c) is preferably a monocyclic radical of five orsix ring atoms having one or two ring nitrogen atoms, such as pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, pyrrolyl,more preferably pyridyl, imidazolyl, pyrazinyl, especially pyridyl.Heterocyclyl group for R^(c) is preferably pyrrolidinyl, pyrrolinyl,imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl,piperazinyl, morpholinyl, pyranyl, tetrahydropyranyl,4,5-dihydro-oxazolyl, sultamyl or 4,5-dihydro-thiazolyl, more preferablymorpholinyl, piperidyl or sultamyl. Further preferred group for R^(c) is2-oxo-2H-pyridin-1-yl optionally substituted by C₁₋₆ alkyl or C₁₋₆alkoxy, especially 2-oxo-2H-pyridin-1-yl.

Especially preferred —B—R^(c) is2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl.

When E is E-2, A is preferably —CONH—.

When E is E-2, preferably R³ and R⁴ are independently from each otherhydrogen, C₁₋₆ alkoxycarbonyl or hydroxy C₁₋₆ alkyl.

When E is E-2, the compounds wherein R⁴ is mono- or di-substitutedamino-carbonyl are also preferred. The compounds wherein R⁴ isdi-substituted amino-carbonyl are more preferred. Preferreddi-substituted amino-carbonyl for R⁴ is —C(O)—NRR′ wherein R is C₁₋₆alkyl, especially methyl, and R′ is hydroxy C₁₋₆ alkyl, especially2-hydroxyethyl. When R⁴ is mono- or di-substituted amino-carbonyl, R³ ispreferably hydrogen.

When E is E-2, the compounds wherein R⁴ is optionally substitutedheterocyclylcarbonyl or optionally substituted heteroarylcarbonyl arealso preferred. The compounds wherein R⁴ is optionally substitutedheterocyclylcarbonyl are more preferred. Heterocyclyl group of“optionally substituted heterocyclylcarbonyl” contains preferably anitrogen atom as a ring member, and the carbonyl carbon atom is bondedto the nitrogen atom of the heterocyclyl group. A preferred optionallysubstituted heterocyclylcarbonyl is, for example, morpholinyl,pyrrolidinyl, 3-hydroxypyrrolidinyl, piperidinyl, 3-hydroxypiperidinyl,4-methylpiperazinyl, azetidinyl. When R⁴ is optionally substitutedheterocyclylcarbonyl or optionally substituted heteroarylcarbonyl, R³ ispreferably hydrogen.

When E is E-2, the compounds wherein —B—R^(c) is2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl, D is 4-chlorophenyl or5-chloro-pyridin-2-yl and A is —CONH— are preferred.

When E is E-2, the compounds wherein A is —CONH—, —B—R^(c) is2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl, D is 4-chlorophenyl or5-chloro-pyridin-2-yl and R³ is hydrogen and R⁴ is mono- ordi-substituted amino-carbonyl, optionally substitutedheterocyclylcarbonyl or optionally substituted heteroarylcarbonyl areespecially preferred. R⁴ is more preferably di-substitutedamino-carbonyl or optionally substituted heterocyclylcarbonyl. Preferreddi-substituted amino-carbonyl for R⁴ is —C(O)—NRR′ wherein R is C₁₋₆alkyl, especially methyl, and R′ is hydroxy C₁₋₆ alkyl, especially2-hydroxyethyl. A preferred optionally substituted heterocyclylcarbonylfor R⁴ is one containing a nitrogen atom as a ring member, and thecarbonyl carbon atom is bonded to the nitrogen atom of the heterocyclylgroup, such as morpholinyl, pyrrolidinyl, 3-hydroxypyrrolidinyl,piperidinyl, 3-hydroxypiperidinyl, 4-methylpiperazinyl, azetidinyl.

When E is E-2, the compounds of the following enantiomeric form arepreferred,

wherein A, B, R^(c)C, D and R³-R⁵ are as defined before.

A is preferably —CONH—,

—B—R^(c) is preferably 2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl,D is preferably 4-chlorophenyl or 5-chloro-pyridin-2-yl and R³ ispreferably hydrogen and R⁴ is preferably mono- or di-substitutedamino-carbonyl, optionally substituted heterocyclylcarbonyl oroptionally substituted heteroarylcarbonyl.

Particularly preferred compounds in this group are:

-   (1RS,2SR)-cyclopropane-1,2-dicarboxylic acid    1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1RS,2SR)-cyclopropane-1,2-dicarboxylic acid    1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1RS,2SR)-1-methyl-cyclopropane-1,2-dicarboxylic acid    2-[(5-chloro-pyridin-2-yl)-amide]1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1SR,2SR,3RS)-2-(4-chloro-phenylcarbamoyl)-3-[4-(2-oxo-2H-pyridin-1-yl)-phenyl-carbamoyl]-cyclopropanecarboxylic    acid ethyl ester,-   (1RS,2SR)-1-methyl-cyclopropane-1,2-dicarboxylic acid    1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1SR,2RS,3SR)-3-hydroxymethyl-cyclopropane-1,2-dicarboxylic acid    1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1SR,2SR,3RS)-2-(4-Chloro-phenylcarbamoyl)-3-[4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylic    acid,-   (1SR,2RS,3SR)-3-(1-Hydroxy-1-methyl-ethyl)-cyclopropane-1,2-dicarboxylic    acid    1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1SR,2RS,3SR)-3-(1-Ethyl-1-hydroxy-propyl)-cyclopropane-1,2-dicarboxylic    acid    1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1RS,2SR,3RS)-3-(Piperidine-1-carbonyl)-cyclopropane-1,2-dicarboxylic    acid    1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1RS,2SR,3SR)-Cyclopropane-1,2,3-tricarboxylic acid    1-[(4-chloro-phenyl)-amide]2-dimethylamide    3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1RS,2SR,3SR)-Cyclopropane-1,2,3-tricarboxylic acid    1-[(4-chloro-phenyl)-amide]3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}2-[(2-hydroxy-ethyl)-methyl-amide],-   (1SR,2RS,3SR)-2-(4-Chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylic    acid ethyl ester,-   (1SR,2RS,3SR)-2-(4-Chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylic    acid,-   (1S,2R,3S)-2-(4-Chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylic    acid ethyl ester,-   (1S,2R,3S)-2-(4-Chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylic    acid,-   (1RS,2SR,3SR)-3-(Morpholine-4-carbonyl)-cyclopropane-1,2-dicarboxylic    acid    1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1R,2S,3S)-3-(Morpholine-4-carbonyl)-cyclopropane-1,2-dicarboxylic    acid    1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1RS,2SR,3SR)-3-(3-Hydroxy-pyrrolidine-1-carbonyl)-cyclopropane-1,2-dicarboxylic    acid    1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1SR,2SR,3RS)-Cyclopropane-1,2,3-tricarboxylic acid 1-amide    2-[(4-chloro-phenyl)-amide]3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1RS,2SR,3SR)-Cyclopropane-1,2,3-tricarboxylic acid    1-[(4-chloro-phenyl)-amide]3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}2-[(2-methoxy-ethyl)-methyl-amide],-   (1SR,2RS,3SR)-Cyclopropane-1,2,3-tricarboxylic acid    1-(carbamoylmethyl-methyl-amide)    2-[(4-chloro-phenyl)-amide]3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1RS,2SR,3SR)-3-(Azepane-1-carbonyl)-cyclopropane-1,2-dicarboxylic    acid    1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1RS,2SR,3SR)-3-(3-Oxo-piperazine-1-carbonyl)-cyclopropane-1,2-dicarboxylic    acid    1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1RS,2SR,3SR)-3-(3,3-Difluoro-pyrrolidine-1-carbonyl)-cyclopropane-1,2-dicarboxylic    acid    1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1SR,2SR,3RS)-Cyclopropane-1,2,3-tricarboxylic acid    1-[(4-chloro-phenyl)-amide]3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}2-[(2,2,2-trifluoro-ethyl)-amide],-   (1RS,2SR,3SR)-Cyclopropane-1,2,3-tricarboxylic acid    1-[(4-chloro-phenyl)-amide]2-diethylamide    3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1RS,2SR,3SR)-3-(Pyrrolidine-1-carbonyl)-cyclopropane-1,2-dicarboxylic    acid    1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1RS,2SR,3SR)-3-(Azetidine-1-carbonyl)-cyclopropane-1,2-dicarboxylic    acid    1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1SR,2SR,3RS)-Cyclopropane-1,2,3-tricarboxylic acid    1-[(4-chloro-phenyl)-amide]2-ethylamide    3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1SR,2SR,3RS)-Cyclopropane-1,2,3-tricarboxylic acid    1-[(4-chloro-phenyl)-amide]2-[(2,2-difluoro-ethyl)-amide]3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1RS,2SR,3SR)-3-(3-Hydroxy-azetidine-1-carbonyl)-cyclopropane-1,2-dicarboxylic    acid-   1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1RS,2SR,3SR)-3-(3-Hydroxy-piperidine-1-carbonyl)-cyclopropane-1,2-dicarboxylic    acid    1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1RS,2SR,3SR)-Cyclopropane-1,2,3-tricarboxylic acid    1-[(4-chloro-phenyl)-amide]2-[(2,3-dihydroxy-propyl)-methyl-amide]3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1RS,2SR,3SR)-3-(4-Hydroxy-piperidine-1-carbonyl)-cyclopropane-1,2-dicarboxylic    acid    1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1RS,2SR,3SR)-3-(4-Methyl-piperazine-1-carbonyl)-cyclopropane-1,2-dicarboxylic    acid    1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1RS,2SR,3SR)-Cyclopropane-1,2,3-tricarboxylic acid    1-[(4-chloro-phenyl)-amide]2-[(2-dimethylamino-ethyl)-methyl-amide]3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1RS,2SR,3RS)-3-(4-Acetyl-piperazine-1-carbonyl)-cyclopropane-1,2-dicarboxylic    acid    1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1RS,2SR,3SR)-3-(4-Dimethylamino-piperidine-1-carbonyl)-cyclopropane-1,2-dicarboxylic    acid    1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1RS,2SR,3SR)-3-(4-Carbamoyl-piperidine-1-carbonyl)-cyclopropane-1,2-dicarboxylic    acid    1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1RS,2SR,3SR)-Cyclopropane-1,2,3-tricarboxylic acid    1-[(4-chloro-phenyl)-amide]2-(dimethylcarbamoylmethyl-methyl-amide)    3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1R,2S,3S)-Cyclopropane-1,2,3-tricarboxylic acid    1-[(4-chloro-phenyl)-amide]2-dimethylamide    3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1R,2S,3S)-Cyclopropane-1,2,3-tricarboxylic acid    1-[(4-chloro-phenyl)-amide]3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}2-[(2-hydroxy-ethyl)-methyl-amide].

Particularly preferred compounds in this group are:

-   (1S,2R,3S)-3-hydroxymethyl-cyclopropane-1,2-dicarboxylic acid    1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1S,2R,3S)-3-pyrrolidin-1-ylmethyl-cyclopropane-1,2-dicarboxylic    acid    1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1S,2R,3S)-3-cyanomethyl-cyclopropane-1,2-dicarboxylic acid    1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1S,2R,3S)-3-methoxymethyl-cyclopropane-1,2-dicarboxylic acid    1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1SR,2RS)-1-cyano-cyclopropane-1,2-dicarboxylic acid    1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1SR,2RS)-1-hydroxymethyl-cyclopropane-1,2-dicarboxylic acid    1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1SR, 2RS)-1-cyano-cyclopropane-1,2-dicarboxylic acid    2-[(5-chloro-pyridin-2-yl)-amide]1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1SR,2RS)-1-hydroxymethyl-cyclopropane-1,2-dicarboxylic acid    2-[(4-chloro-phenyl)-amide]1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide},-   (1R,2S)-1-methyl-cyclopropane-1,2-dicarboxylic acid    2-[(5-chloro-pyridin-2-yl)-amide]1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenyl]-amide},-   (1S,2R,3R)-3-hydroxymethyl-cyclopropane-1,2-dicarboxylic acid    1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.

Another preferred compound of the invention is a compound of Formula (I)wherein E is E-3.

When E is E-3, D is preferably aryl optionally substituted by onehalogen atom selected from chlorine and bromine or heteroaryl optionallysubstituted by one halogen atom selected from chlorine and bromine. Morepreferred halogen atom is chlorine. Aryl group for D is preferablyphenyl. Heteroaryl group for D is preferably monocyclic or bicyclicradical of 5 to 12 ring atoms having at least one aromatic ringcontaining one or two ring heteroatoms selected from N and S, such aspyrrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl,imidazolyl, tetrazolyl, thienyl, isothiazolyl, indolyl, isoindolyl,indolizinyl, indazolyl, quinolyl, isoquinolyl, more preferably pyridyl,thienyl, pyrimidinyl, pyridazinyl or indolyl, especially phenyl orpyridyl.

When E is E-3, D is further more preferably chlorophenyl orchloropyridyl, especially 4-chlorophenyl or 5-chloro-pyridin-2-yl.4-chlorophenyl is especially preferred.

When E is E-3, B is preferably optionally substituted phenyl oroptionally substituted heteroaryl. Heteroaryl group for B is preferablya monocyclic radical of five or six ring atoms having one or two ringnitrogen atoms, such as pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,pyrazolyl, imidazolyl, pyrrolyl, especially pyridyl. B is morepreferably phenyl or pyridyl, especially phenyl, optionally substitutedby one or two halogen atoms selected independently from the groupconsisting of chlorine, fluorine and bromine. Further more preferredgroup for B is a phenyl substituted by one or two fluorine, especiallyone fluorine. 2-fluorophenyl is especially preferred.

When E is E-3, R^(c) is preferably aryl, heteroaryl or heterocyclyl, onecarbon atom of said aryl, heteroaryl or heterocyclyl ring optionallybeing replaced with a carbonyl group, and said aryl, heteroaryl orheterocyclyl ring optionally being substituted by hydroxy, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ alkyl sulfonyl, amino C₁₋₆ alkyl, mono-C₁₋₆ alkylsubstituted amino-C₁₋₆ alkyl or di-C₁₋₆ alkyl substituted amino-C₁₋₆alkyl, more preferably R^(c) is aryl, heteroaryl or heterocyclyl, onecarbon atom of said aryl, heteroaryl or heterocyclyl ring being replacedwith a carbonyl group at ortho position with respect to B, and saidaryl, heteroaryl or heterocyclyl ring optionally being substituted byhydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkyl sulfonyl, amino C₁₋₆ alkyl,mono-C₁₋₆ alkyl substituted amino-C₁₋₆ alkyl or di-C₁₋₆ alkylsubstituted amino-C₁₋₆ alkyl. Aryl group for R^(c) is preferably phenyl.Heteroaryl group for R^(c) is preferably a monocyclic radical of five orsix ring atoms having one or two ring nitrogen atoms, such as pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, pyrrolyl,more preferably pyridyl, imidazolyl, pyrazinyl, especially pyridyl.Heterocyclyl group for R^(c) is preferably pyrrolidinyl, pyrrolinyl,imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl,piperazinyl, morpholinyl, pyranyl, tetrahydropyranyl,4,5-dihydro-oxazolyl, sultamyl or 4,5-dihydro-thiazolyl, more preferablymorpholinyl, piperidyl or sultamyl. Further preferred group for R^(c) is2-oxo-2H-pyridin-1-yl optionally substituted by C₁₋₆ alkyl or C₁₋₆alkoxy, especially 2-oxo-2H-pyridin-1-yl.

Especially preferred —B—R^(c) is2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl.

When E is E-3, A is preferably —CONH—.

When E is E-3, the compounds wherein —B—R^(c) is2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl, D is 4-chlorophenyl and A ispreferably —CONH— are especially preferred.

Particularly preferred compounds in this group are:

-   N1-(4-Chloro-phenyl)-N-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-succinamide,-   N4-(4-Chloro-phenyl)-N1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-2,2-dimethyl-succinamide,-   (4-Chloro-phenyl)-3,3-dimethyl-4-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-4-oxo-butyramide,-   (R)—N4-(4-Chloro-phenyl)-N1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-2-hydroxy-succinamide,-   (4-chloro-phenyl)-[2-fluoro-4-(3-oxo-morpholin-4-yl)-phenyl]-2,2-dimethyl-succinamide,-   (S)-(4-Chloro-phenyl)-[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenyl]-2-hydroxy-2-methyl-succinamide,-   (R)—N1-(4-Chloro-phenyl)-N-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-2-hydroxy-succinamide,-   (S)—N1-(4-Chloro-phenyl)-N-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-2-hydroxy-succinamide,-   (R)—(4-Chloro-phenyl)-[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenyl]-2-hydroxy-2-methyl-succinamide,-   (S)—N-4-(4-Chloro-phenyl)-N1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-2-hydroxy-succinamide.

Also within the scope of the present invention are intermediatecompounds, for example, an enantiomerically pure compound with formula

or compounds with the formula

whereinB is optionally substituted phenyl, optionally substituted heteroaryl oroptionally substituted heterocyclyl;R^(c) is optionally substituted aryl, optionally substituted heteroarylor optionally substituted heterocyclyl, one or two carbon atoms of saidaryl, heteroaryl or heterocyclyl ring optionally being replaced with acarbonyl group; andD is aryl optionally substituted by one, two or three halogen atomsindependently selected from chlorine, fluorine and bromine or heteroaryloptionally substituted by one, two or three halogen atoms independentlyselected from chlorine, fluorine and bromine.

The compounds of the present invention can be prepared, for example, bythe general synthetic procedures described below.

General Synthetic Procedures

Abbreviations:

BOP: Benzotriazolyl-N-oxy-tris(dimethylamino)-phosphoniumhexafluorophosphateBOP-Cl: Bis-(2-oxo-3-oxazolidinyl)-phosphinic acid chloride

CDI: Carbonyldiimidazole DCC: N,N′-Dicyclohexylcarbodiimide DIC:N,N′-Diisopropylcarbodiimide DMA: N,N-Dimethylacetamide DMF:N,N-Dimethylformamide

EDC: N-(3-Dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochlorideEEDQ: N-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinolineHATU: O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphateHBTU: O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate

HOBt: N-Hydroxybenzotriazole

MCPBA: m-Chloroperbenzoic acid

NMP: N-methylpyrrolidone

PyBOP: Benzotriazol-1-yl-oxytripyrrolidinephosphoniumhexafluorophosphatePyBrOP: Brom-tripyrrolidinophosphonium hexafluorophosphateTBTU: O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumterafluoroborate

THF: Tetrahydrofurane 1. Synthesis of Cyclopentane DicarboxamideDerivatives (Racemic) a) Synthesis of Key Intermediates Trans- andCis-Ketones and Epoxides

The mono saponification of methylene-cyclopentane-1,2-dicarboxylic aciddiethyl ester (available by the method described by B. M. Trost et al.,J. Am. Chem. Soc., 105, 2315, 1983) can be effected by dissolving it ina suitable solvent like MeOH, EtOH, THF, 1,4-dioxane, water or mixturesthereof and a base like LiOH, NaOH, KOH, Na₂CO₃, K₂CO₃ or Cs₂CO₃,preferably MeOH and K₂CO₃.

The mono acid is dissolved in a suitable solvent like dichloromethane,DMF, acetonitrile, THF, NMP, DMA, etc. and activated with an amidecoupling reagent like EDC, DIC, DCC, CDI, TBTU, HBTU, EEDQ, HOBt, HATU,PyBOP, PyBrOP, BOP, BOP-Cl, etc. in the presence of a base like NEt₃,hünigs base, N-methylmorpholine etc. at −20° C. to 120° C. By adding oneto two equivalents of the amine D-NH₂ the corresponding monoamide isobtained after reaction for 0.5-120 h at −20° C. to 120° C.Alternatively, transformation of the acid into the corresponding acidchloride or anhydride by means of oxalyl chloride, thionylchloride,isobutylcarbamoyl chloride or related reagents and a base like NEt₃,hünigs base, N-methylmorpholine etc, and reaction with D-NH₂ (all D-NH₂commercially available) yields also the corresponding monoamide. Thepreferred conditions involve THF, EDC, HOBt and NEt₃.

Saponification of the ester group can be effected as described above.The second amide group can be introduced as described above usingR^(c)—B—NH₂, the preferred method involves isobutylcarbamoyl chloride asactivating agent and N-methylmorpholine as base at −20 to 60° C. Thetrans- and cis-isomers can be separated by chromatography on silica.

Preparation of the aniline derivative R^(c)—B—NH₂ can be carried outaccording to the method described by C. F. Bigge et al. (patentapplication WO 2003045912).

Conversion of the olefine to the ketone group by periodate cleavage canbe accomplished under standard conditions using OSO₄ and NaIO₄ in asolvent like an alcohol e.g. MeOH and water at 0° to 70° C. preferablyat 20° C. for 1 to 20 h.

Epoxidation of the olefine can be accomplished with an oxidizing agentsuch as peracids, e.g. MeCOOOH or MCPBA in a solvent like e.g. CH₂Cl₂ at0 to 50° C., preferably at 20° C. to give a mixture of epimers which canbe separated by chromatography on silica.

b) Modifications of the Trans- and Cis-Ketones

G in the scheme is mono or di-substituted amino as defined before.Reductive amination of the ketone with HG (all bases commerciallyavailable) can be accomplished with a reducing agent such as e.g. NaBH₄,LiBH₄, Li(CN)BH₃ or preferably Na(CN)BH₃ in a solvent such as analcohol, e.g. MeOH or an ether, e.g. THF and an acid e.g. HCl, H₂SO₄,H₃PO₄ or a carboxylic acid, preferably CH₃COOH at a temperature of −10to 60° C., preferably at 20° C. for 1-40 h. The products obtainedconsist of a mixture of epimers at the newly formed stereo center.

Acylation and sulfonylation can be performed by reaction of the aminewith a chloroformate, nitrophenylformate or a sulfochloride in thepresence of a base, e.g. NEt₃ or preferably N,N-diisopropylethylamine ina solvent such as e.g. THF, CH₂Cl₂ or preferably CH₃CN at −10 to 60° C.,preferably at 20° C. for 1-40 h. The products obtained consist of amixture of epimers at the G stereo center.

Reduction of the ketone to the alcohol can be effected by reducingagents e.g. Li(CN)BH₃, Na(CN)BH₃, LiBH₄ or preferably NaBH₄ in a solventsuch as e.g. MeOH or preferably THF at a temperature of −10 to 60° C.,preferably at 20° C. for 1-40 h. The products obtained consist of amixture of epimers at the newly formed stereo center.

c) Modifications of the Trans-Epoxide

G in the scheme is mono- or di-substituted amino as defined before. R′³is hydrogen or C₁₋₆ alkyl.

Ring-opening of the epoxide with HG can be accomplished in an alcohol assolvent such as MeOH, EtOH, PrOH etc., preferably EtOH at a temperatureof 20 to 120° C. for 1-40 h. Sulfonylation of the amines can beperformed as described above. The products obtained consist of a mixtureof epimers at the alcohol stereo center.

Ring-opening of the epoxide with R′³OH, particularly R′³═H can beeffected in the presence of a mineral acid such as HCl, H₂SO₄, H₃PO₄ ora carboxylic acid, e.g. CH₃COOH, preferably H₂SO₄ in a solvent mixturesuch as THF/water at 0 to 100° C., preferably at 20° C. for 1 to 40 h.For R′³═C₁₋₆ alkyl the reaction can be performed in the presence of aLewis acid e.g. BF₃.OEt₂ using the alcohol R′³OH as the solvent at 0 to100° C., preferably at 20° C. for 1 to 40 h. The products obtainedconsist of a mixture of epimers at the alcohol stereo center.

Ring-expansion of the epoxide can be accomplished with 2-chloroethanolas R¹³OH in the presence of BF₃.OEt₂ as described above followed bycyclization of the intermediate chloroalcohol using KI as activatingagent and a strong base such as LiOH, NaOH, KOH, preferably NaOH in asolvent mixture of CH₃CN and water at 50 to 150° C. in a microwaveapparatus. The products obtained consist of a mixture of epimers at theether stereo center.

Reductive ring-opening of the epoxide can be effected according to A.Heydari et al. (Synthesis, 10, 1563, 2004) with a reducing agent such asBH₃ or preferably BH₃.NEt₃ in the presence of a promoter such as LiClO₄in Et₂O as the solvent at 0 to 50° C., preferably at 20° C. for 1-40 h.The products obtained consist of a mixture of epimers at the alcoholstereo center.

d) Modifications of the Amide Group

G in the scheme is mono or di-substituted amino as defined before.

Curtius rearrangement (step i) ofmethylene-cyclopentane-1,2-dicarboxylic acid ethyl ester to thet-butyloxycarbonyl protected amine was accomplished withdiphenylphosphoryl azide and an amine, e.g. NEt₃ in a solvent such asbenzene or preferably toluene at 20 to 150° C., preferably at 80° C. for1-40 h. The intermediate isocyanate can be trapped with an alcohol suchas MeOH, EtOH or preferably t-BuOH at 20 to 150° C., preferably at 80 to90° C.

Saponification (step ii) and amide formation (step iii) can beaccomplished as described in the synthetic procedure 1a).

Deprotection (step iv) can be effected with a mineral acid such as HCl,H₂SO₄ or H₃PO₄ or a carbonic acid, preferably CF₃COOH in a solvent suchas CH₂Cl₂ at 0 to 60° C., preferably at 20° C. for 1-40 h.

Amide formation (step v) using R^(c)—B—COOH, which can be preparedaccording to the method described by C. F. Bigge et al. (patentapplication WO 2003045912) and steps vi-ix can be carried out asdescribed in the synthetic procedures 1a) and 1b). The products obtainedconsist of a mixture of epimers at the newly formed stereo center.

Et in the schemes under procedure 1.a) to d) can be replaced withanother C₁₋₆ alkyl group, preferably C₁₋₄ alkyl group. B, R^(c) and D inthe schemes under procedure I.a) to d) are as defined before. D ispreferably 4-chloro phenyl. —B—R^(c) is preferably2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl.

2. Synthesis of Cyclopentane Dicarboxamide Derivatives (Homochiral) a)Synthesis of Key Intermediates Trans-Ketones and Epoxides

The resolution of racemic trans-methylene-cyclopentane-1,2-dicarboxylicacid diethyl ester via mono saponification can be accomplished withlipase PN from Phycomyces nitens to afford the enantiomerically pureS,S-diethyl ester as retained enantiomer.

The following selective mono saponification with lipase OF from Candidarugosa delivered the enantiomerically pure S,S-monoethyl ester. The usedhydrolases were selected from a set of selective ones (like e.g. lipaseG from Penicilium camenberti, lipase N from Rhizopus niveus or lipase PNfrom Phycomyces nitens) and active ones (like e.g. lipase OF fromCandida rugosa, lipase RMM from Rhizomucor miehei, esterase PLE from pigliver or protease Subtilisin A from Bacillus licheniformis) discoveredin a library out of 118 commercially available enzymes. Interestingly,the esterase from pig liver, which was used in a resolution of racemictrans-4-oxo-cyclopentane-1,2-dicarboxylic acid diethyl ester publishedby A. Rosenquist et al. (Acta Chem. Scan., 46, 1127, 1992), turned outto be not enantioselective for the resolution of racemictrans-methylene-cyclopentane-1,2-dicarboxylic acid diethyl ester.

Both enzymatic hydrolysis steps were performed as emulsion of thesubstrates in an aqueous buffer system. During the reaction the selectedpH-value was maintained by controlled addition of a base. Theselectivity and/or activity could be influenced by the addition of saltsor organic solvents or by lowering the reaction temperature as shown inthe preparative example. The work up of the products was achieved byconventional extractive procedures with different organic solvents at aproper pH-value.

Conversion of the mono acid to the ketone and epoxide epimers can becarried out as described in the synthetic procedures 1a)

b) Modifications of the Epoxide and Olefine

Ring opening of the epoxide can be effected as described in thesynthetic procedure 1c). Both epimers are available as single isomer.

Cyclopropanation of the olefine can be carried out according to themethod described by H. E. Simmons and R. D. Smith (J. Am. Chem. Soc. 80,5323, 1958) involving diethylzinc, CH₂I₂ and trifluoroacetic acid in asolvent such as toluene or CH₂Cl₂ or a mixture thereof.

c) Modifications of the Intermediate Keto- and Hydroxyl-Esters

In a different strategy, modifications of the keto- and hydroxyl-groupcan be effected prior to the introduction of —B—R^(c), since e.g. theintermediate epimers of the hydroxyester (only one epimer depicted inthe scheme) can be conveniently separated.

Periodate cleavage of the olefine (step i) followed by reduction of theketone (step ii) can be performed as described in the syntheticprocedures 1a) and 1b). The hydroxyester epimers are separable bychromatography on silica.

Fluorination of the alcohol (step iii) with inversion of theconfiguration can be carried out with diethylamino sulphur trifluorideor preferably with bis-(2-methoxyethyl)-aminosulphur trifluoride inCH₂Cl₂ at −80 to 20° C.

Saponification of the ester (step iv) can be carried out as described inthe synthetic procedure 1a). Amide formation by reaction of the acidwith R^(c)—B—NH₂ (step v) can be accomplished as described in thesynthetic procedure 1a) preferably by using isobutylcarbamoyl chlorideas the activating agent.

Fluorination of the ketone (step vi), saponification (step vii) andsubsequent amide formation with R^(c)—B—NH₂ (step viii) can beaccomplished as described for step iii)-v).

Alternatively, the hydroxyester can be converted to the amide withR^(c)—B—NH₂ (step ix) with AlMe₃ according to the method of M. Weinrebet al. (Tetrahedron Lett., 48, 4171, 1977). The relative and absoluteconfiguration of the amide shown in the scheme was determined by anX-ray analysis of the amide complexed with factor Xa.

The alcohol group can be converted to the methylether (step x) usingMeCl, MeBr or preferably MeI in a solvent like THF or MeCN, preferably amixture of both and an additive such as AgO at 0-40° C. preferably at20° C. Amide formation (xi) can be accomplished according to step ix)using AlMe₃. Both epimers of the ethers are available as pure isomers.

d) Modifications of D

Amide formation by reaction of the acid with R^(c)—B—NH₂ can beaccomplished as described in the synthetic procedures 1a), the preferredmethod involves isobutylcarbamoyl chloride as activating agent andN-methylmorpholine as base at −20 to 60° C., preferably at 45° C.

The second amide group can be introduced by reaction of the ester withD-NH₂ in the presence of AlMe₃ as described in the synthetic procedure2c).

e) Modifications of —B—R^(c)

The second amide group can be introduced by reaction of the ester withR^(c)—B—NH₂ in the presence of AlMe₃ as described in the syntheticprocedure 2c). Preparation of the anilines R^(c)—B—NH₂ are described inC. F. Bigge et al. (patent application WO 2003045912); R. A. Galemmo etal. (patent application WO9857937); M. L. Quan et al. (patentapplication WO 2003047517); I. Zeid et al. (Journal de la SocieteAlgerienne de Chimie 4(2), 171, 1994.

Et in the schemes under procedure 1.a) to e) can be replaced withanother C₁₋₆ alkyl group, preferably C₁₋₄ alkyl group. B, R^(c) and D inthe schemes under procedure 2.a) to e) are as defined before. D ispreferably 4-chlorophenyl. —B—R^(c) is preferably2-fluoro-4-(2-oxo-2H-pyridin-1-yl)phenyl.

3. Synthesis of cyclopropane dicarboxamide derivatives via succinimide

B, R^(c) and D are as defined before.

Preferably D is 4-chlorophenyl. Preferably —B—R^(c) is2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl. In a suitable solvent such ase.g. acetonitrile, maleic anhydride 1 is treated with D-NH₂ orR^(c)—B—NH₂ to give amido carboxamide-carboxylic acids 2a or 2b,respectively (steps a/b). They can be converted to the cyclic imides3a/b, respectively, e.g. by treatment with an acid (e.g. HCl) a LewisAcid (e.g. ZnCl₂) or an anhydride (e.g. acetic anhydride) in analogy toe.g. Pal et al., Synthesis, 10, 2003, 1549; Yoshitake et al., J. Chem.Soc. Perkin II, 2002, 1611; Dubovchich et al., Bioorg. Med. Chem. Lett.,12, 2002, 1529; Shin et al., Tet. Lett., 42, 7, 2001, 1325 (steps c/d).Cyclopropanation of 3a/b to racemic 4a/b, respectively (R^(I)═C₁₋₆alkyl), is usually carried out by treatment with an α-diazo acetic acidalkyl ester (preferably α-diazo acetic acid ethyl ester) in a solventsuch as e.g. toluene or xylene at 80-160° C., though conditionsanalogous to those described e.g. by Kozhushkov et al., Synthesis, 2003,956; Kurihara et al., Heterocycles 20, 1983, 1919, or Saegusa et al., J.Org. Chem. 38, 1973, 2319 may also be used (steps e/f). The racemiccyclopropano-imides 4a/b are then treated with R^(C)—BNH₂ or DNH₂,respectively, to give racemic opened derivative 5 (step g/h). Usuallythis is carried out in a suitable solvent such as DMF, whereas usuallyR^(C)—BNH₂/DNH₂ is previously deprotonated with a strong base such ase.g. NaH. The ester moiety can be derivatized to various functionalgroups (leading to racemic 6, step i) using methods generally known tothose skilled in the art. Some typical examples are given below:

Hydrolysis of racemic 5 (e.g. with aq. LiOH) leads to the correspondingcarboxylic acid (R^(II)═COOH) which can be converted into amides (e.g.R^(II)═CONMe₂) by treatment with a suited amine and a condensatingreagent such as e.g. DCC (dicyclohexylcarbodiimide) or EDCI(N-3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride).

Treatment of racemic 5 with an excess of an alkyllithium oralkylmagnesiumhalide leads to derivatives with R^(II)═C(C₁₋₆ alkyl)₂OH.Reduction of racemic 5 (e.g. with NaBH₄ in MeOH) leads to the derivativewith R^(II)═CH₂OH that can be oxidized to the aldehyde (R^(II)═CHO) e.g.by a Swern-oxidation. Treatment of derivatives with R^(II)═CH₂OH with asulfonylating agent such as e.g. mesylchloride, tosylchloride, triflicanhydride leads to intermediates with e.g. R^(II)═CH₂O Ms, CH₂OTs,CH₂OTf that can be reacted with a nucleophile “Nu or NuH” such as e.g.an amine or a heterocycle (e.g. imidazole) to give derivatives withR^(II)═CH₂—Nu. Derivatives obtained by this method for whichR═CH₂—NHC₁₋₆ alkyl¹ are readily converted to derivatives withR^(II)═CH₂—NC₁₋₆ alkyl¹(SO₂C₁₋₆ alkyl²), R^(II)═CH₂—NC₁₋₆ alkyl¹(COC₁₋₆alkyl²), with R^(II)═CH₂—NC₁₋₆ alkyl¹(COOalkyl²) by treatment with areagent C₁—SO₂C₁₋₆ alkyl², ClCO C₁₋₆ alkyl², ClCOOC₁₋₆ alkyl²,respectively, preferably in the presence of a base such as e.g.triethylamine.

Derivatives with R^(II)═CHO, COOH, CONHR^(III) (wherein R^(III)═H orC₁₋₆ alkyl) may readily be transformed (in one or more steps) intoderivatives with R^(II)=heterocycle using methodologies analogous tothose described or mentioned e.g. in “Advances in Heterocyclicchemistry, Monograph series by A. Katritzky (Editor) and ComprehensiveHeterocyclic Chemistry II, a review of Literature 1982-1995, MonographSeries by A. Katritzky (editor); for more specific examples (e.g.oxazolidines) see e.g.: Cwik et al., Tet. Lett., 43, 2002, 3985;Vorbrueggen et al., Tetrahedron, 49, 1993, 9353.

Alternatively, the COOR¹-group of racemic 4a/b may be transformed to theabove mentioned groups R^(II) (step j, leading to racemic 7a/b) prior tothe R^(c)—BNH₂/DNH₂-promoted imide opening using the same methodsdescribed for step i. The imide opening of 7a/b to racemic 6 is carriedout thereafter (steps k/l) in analogy to steps g/h. If desired orrequired separation of the enantiomers of the racemic 4a/b, 5, 6, or7a/b can be carried out by suitable chiral HPLC. Steps g-l may, ifdesired, be carried out on enantiomerically pure 4a/b, 5 or 7a/b aswell.

4. Synthesis of Cyclopropane Dicarboxamide Derivatives Via SuccinicAnhydrides

R³ to R⁶ in the scheme are hydrogen, C₁₋₆ alkyl or C₃₋₇ cycloalkyl. B,R^(c) and D are as defined before.

Preferably D is 4-chlorophenyl. Preferably —B—R^(c) is2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl. Diacids 1 (CommerciallyAvailable or Known from the Literature) which can exist as mixture ofthe racemic cis isomer and the racemic trans isomer are converted to theracemic cis anhydrides 2 by treatment with neat acetic anhydride atreflux temperature or with trifluoroacetic anhydride at 0° (scheme 1,step a). The trans diacids cannot react to the corresponding anhydrides.The racemic cis anhydrides 2 are separated off by destillation.Alternatively, the reaction mixture is concentrated and the crudeproduct is used for the next step without further purification. Racemicanhydrides 2 are reacted with anilines D-NH₂ in an inert solvent such asTHF to give racemic cyclopropane monocarboxamides 3 (step b). Theproducts resulting from attack at the less hindered carbon are formedpredominantly. Esterification of monocarboxamides 3 (step c) is usuallyaccomplished by dissolving them in an alcohol such as MeOH and EtOHfollowed by treatment with thionyl chloride at 0° C. in analogy to J.Ind. Chem. Soc. 1992, 69(10), 683-4. Racemic esters 4 are then reactedwith anilines R^(c)—B—NH₂ (step d). Anilines are preactivated with AlMe₃in a solvent such as toluene or dioxane and then treated with an ester 4at elevated temperature (usually 90° C.) to give racemic1,2-cyclopropandicarboxamides 5.

5. Synthesis of Cyclopropane Dicarboxamide Derivatives ViaIntramolecular Cyclopropanation

B, R^(c) and D are as defined before.

An Allylester derivative 1, wherein R¹═COC₁₋₆ alkyl, COOC₁₋₆ alkyl orCOOallyl and R^(II)═H, C₁₋₆ alkyl or a suitably O-protectedhydroxymethyl, is converted to the diazo derivative 2 using a diazotransfer reagent such as e.g. tosylazide, diphenylphosphorylazide or4-acetamidobenzensulfonyl azide in the presence of a base such as e.g.N,N-ethyldiisopropylamine (step a). Optionally, for derivatives withR^(I)═COC₁₋₆ alkyl a deacylation to R^(I)═H may be carried out bytreatment with e.g. LiOH (step b). Intramolecular cyclopropanation e.g.using a chiral or a achiral catalyst derived e.g. from rhodium, copper,cobalt or ruthenium (as described e.g. in J. Med. Chem. 2004,47, p456-66, Chem. Commun. 1997, p 211-2, Org. Lett. 2002, p 1911-4, Tet.Lett, 2001, p 2521-4, Ang. Chem. Int. Ed. 1999, p 700-2.) leads to theracemic or enantiomerically enriched (up to >98% ee) bicyclic lactonederivative 3 (step c). Alternatively, for R^(I)═COC₁₋₆ alkyl, COO C₁₋₆alkyl, COOallyl, Allylester 1 can be directly transformed into lactone3, e.g. by treatment with 12 in presence of K₂CO₃ as described e.g. byToeke et al. in Tetrahedron 1993, 49, p 5133-46, or by treatment with achloro-, bromo, iodo-, methanesulfonyloxy- ortrifluormethanesulfonyloxy-methyloxirane after deprotonation of 1 with astrong base such as e.g. NaH as described e.g. by Burgess et al. in J.Org. Chem. 1992, 57, p 5931-6. The lactone 3 can be converted to theanhydride 4 by treatment with an oxidizing agent such as e.g. Jonesreagent, pyridinium dichromate, pyridinium chlorochromate and subsequenttreatment with a dehydrating agent such as e.g. thionylchloride oroxalylchloride (step d). Treatment of the anhydride 4 with eitherH₂N—B—R^(c) or H₂N-D in the presence of a base such as e.g. pyridineleads to the amido carboxylic acids 5 (step e) and 6 (step f),respectively, or mixtures of the two (attack of the amine usuallyoccurring preferentially at the sterically less hindered carbonylgroup). Both 5 and 6 can be converted to the methyl esters 7 and 8 bytreatment with thionylchloride in MeOH or with iodomethane in presenceof potassium carbonate (steps g and h) or to the imides 9 and 10 (stepsi and j), respectively, by treatment with a dehydrating agent such ase.g. thionylchloride. Amido carboxylic acids 11 and 12 can be obtainedby opening of the lactone 3 with either H₂N—B—R^(c) or H₂N-D (previouslytreated with a strong base such as e.g. lithiumbis(trimethylsilyl)amide) and subsequent oxidation of the resultingalcohol using a oxidative agent such as e.g. Jones reagent (steps k and1). In analogy to steps g or h they can be converted to thecorresponding methylesters 13 or 14 (steps m and n) or to the imides 9or 10 (steps o and p).

Esters 7 and 13 are reacted with H₂N—B—R^(c) or H₂N-D, respectively(preactivated with AlMe₃) to bisamide 15 (steps q and r). Similarlyesters 8 and 14 are reacted to bisamide 16 (steps and t). Bisamide 15may alternatively be obtained by reaction of imide 9 with H₂N—B—R^(c)previously pretreated with a strong base such as e.g. lithiumbis(trimethylsilyl)amide (step u), bisamide 16 by reaction of imide 10with H₂N-D (pretreated with a strong base such as e.g. lithiumbis(trimethylsilyl)amide (step v). These reactions are usually carriedout in an inert solvent such as THF, dioxane or toluene at temperaturesranging from RT to 150° C.

If desired R^(I) may be derivatized to other functional groups. Typicaltransformations are e.g.: Hydrolysis of R¹═COOC₁₋₆ Alkyl to R¹═COOH withe.g. LiOH, reduction of R¹═COOC₁₋₆ Alkyl to R¹═CH₂OH with e.g. NaBH₄.Derivatives with R¹═COOH can be converted into amides (e.g. R¹═CONMe₂)by treatment with a suited amine and a condensating reagent such as e.g.DCC (dicyclohexylcarbodiimide) or EDCI(N-3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride). Treatmentof derivatives with R═CH₂OH with a sulfonylating agent such as e.g.mesylchloride, tosylchloride, triflic anhydride leads to intermediateswith e.g. R^(II)═CH₂O Ms, CH₂OTs, CH₂OTf that can be reacted with anucleophile “Nu or NuH” such as e.g. an amine, a heterocycle, or asource of a cyanide or a fluoride anion, or a heterocycle, to givederivatives with R^(I)═CH₂—Nu. R^(I) or R^(II)═CH₂OH can be oxidized toR^(I) or R^(II)═CHO e.g. by a Swern-oxidation and derivatized to R^(I)or R^(II)═C₁₋₆ alkyl by Wittig-type reaction and subsequenthydrogenation of the double bond.

For derivatives with R^(II)=suitably protected hydroxymethyl,deprotection may be carried out to R^(II)═CH₂OH using standardprocedures commonly known to those in the art (e.g. desilylation withTBAF, or de-paramethoxybenzylation with DDQ) and e.g. oxidized toR^(II)═COOH or formyl. R^(II)═CH₂OH, COOH or formyl can be furtherderivatized using the same methodologies described above for R^(I)═CH₂OHor COOH.

As described above, the compounds of formula (I) are active compoundsand inhibit the coagulation factor Xa. These compounds consequentlyinfluence both platelet activation which is induced by this factors andplasmatic blood coagulation. They therefore inhibit the formation ofthrombi and can be used for the treatment and/or prevention ofthrombotic disorders, such as, amongst others, arterial and venousthrombosis, deep vein thrombosis, peripheral arterial occlusive disease(PAOD), unstable angina pectoris, myocardial infarction, coronary arterydisease, pulmonary embolism, stroke (cerebral thrombosis) due to atrialfibrillation, inflammation and arteriosclerosis. The compounds of thepresent invention can also be used in the treatment of acute vesselclosure associated with thrombolytic therapy and restenosis, e.g. aftertransluminal coronary angioplasty (PTCA) or bypass grafting of thecoronary or peripheral arteries and in the maintenance of vascularaccess patency in long term hemodialysis patients. F.Xa inhibitors ofthis invention may form part of a combination therapy with ananticoagulant with a different mode of action or with a plateletaggregation inhibitor or with a thrombolytic agent. Furthermore, thesecompounds have an effect on tumor cells and prevent metastases. They cantherefore also be used as antitumor agents.

Prevention and/or treatment of thrombotic disorders, particularlyarterial or deep vein thrombosis, is the preferred indication.

The invention therefore also relates to pharmaceutical compositionscomprising a compound as defined above and a pharmaceutically acceptableexcipient.

The invention likewise embraces compounds as described above for use astherapeutically active substances, especially as therapeutically activesubstances for the treatment and/or prophylaxis of diseases which areassociated with the coagulation factor Xa, particularly astherapeutically active substances for the treatment and/or prophylaxisof thrombotic disorders, arterial thrombosis, venous thrombosis, deepvein thrombosis, peripheral arterial occlusive disease, unstable anginapectoris, myocardial infarction, coronary artery disease, pulmonaryembolism, stroke due to atrial fibrillation, inflammation,arteriosclerosis, acute vessel closure associated with thrombolytictherapy or restenosis, and/or tumor

In another preferred embodiment, the invention relates to a method forthe therapeutic and/or prophylactic treatment of diseases which areassociated with the coagulation factor Xa, particularly for thetherapeutic and/or prophylactic treatment of thrombotic disorders,arterial thrombosis, venous thrombosis, deep vein thrombosis, peripheralarterial occlusive disease, unstable angina pectoris, myocardialinfarction, coronary artery disease, pulmonary embolism, stroke due toatrial fibrillation, inflammation, arteriosclerosis, acute vesselclosure associated with thrombolytic therapy or restenosis, and/ortumor, which method comprises administering a compound as defined aboveto a human being or animal subject suffering from a disease associatedwith the coagulation factor Xa.

The inhibition of the coagulation factor Xa by the compounds of thepresent invention can be demonstrated with the aid of a chromogenicpeptide substrate assay such as described in the Examples hereinafter.

The activity of the low molecular weight substances can, moreover, becharacterized in the “prothrombin time” (PT) clotting test. Thesubstances are prepared as a 10 mM solution in DMSO and thereafter madeup to the desired dilution in the same solvent. Thereafter, 0.25 ml ofhuman plasma (obtained from whole blood anticoagulated with 1/10 volumeof 108 mM Na citrate) was placed in the instrument-specific samplecontainer. In each case 5 μl of each dilution of the substance-dilutionseries was then mixed with the plasma provided. This plasma/inhibitormixture was incubated at 37° C. for 2 minutes. Thereafter, there werepipetted to the semi-automatic device (ACL, Automated CoagulationLaboratory (Instrument Laboratory)) 50 μl of plasma/inhibitor mixture inthe measurement container. The clotting reaction was initiated by theaddition of 0.1 ml of Dade® Innovin® (recombinant human tissue factorcombined with calcium buffer and synthetic phospholipids, Dade Behring,Inc., Cat. B4212-50). The time up to the fibrin cross-linking wasdetermined photooptically from the ACL. The inhibitor concentration,which brought about a doubling of the PT clotting time, was determinedby fitting the data to an exponential regression (XLfit).

The compounds of the present invention can furthermore be characterisedby the Activated Partial Thromboplastin time (aPTT). This coagulationtest can e.g. be run on the ACL 300 Coagulation System (InstrumentationLaboratory) automatic analyzer. The substances are prepared as a 10 mMsolution in DMSO and thereafter made up to the desired dilution in thesame solvent. The test is performed with the Dade® Actin® FS ActivatedPTT reagent (purified soy phosphatides in 1.0×10⁻⁴M ellagic acid,stabilizers and preservative, Dade Behring, Inc., Cat. B4218-100)Thereafter, 0.25 ml aliquots of human plasma (obtained from whole bloodanticoagulated with 1/10 volume of 108 mM Na citrate) are spiked with 5μl of test compound in at least 6 concentrations. 501l plasma at 4° C.containing 1/50 vol. inhibitor in solvent are incubated with 50 μl Dade®Actin® FS Activated PTT reagent in water at 37° C. for 3 min., then 50μl CaCl2.2H2O 25 mM in water at 37° C. are added. The time up to thefibrin cross-linking was determined photooptically from the ACL. Theinhibitor concentration, which brought about a doubling of the APTTclotting time, was determined by fitting the data to an exponentialregression (XLfit).

The Ki values of the active compounds of the present inventionpreferably amount to about 0.001 to 50 μM, especially about 0.001 to 1μM. The PT values preferably amount to about 0.5 to 100 μM, especiallyto about 0.5 to 10 μM. The aPTT values preferably amount to about 0.5 to100 μM, especially to about 0.5 to 10 μM.

The compounds of formula I and/or their pharmaceutically acceptablesalts can be used as medicaments, e.g. in the form of pharmaceuticalpreparations for enteral, parenteral or topical administration. They canbe administered, for example, perorally, e.g. in the form of tablets,coated tablets, dragees, hard and soft gelatine capsules, solutions,emulsions or suspensions, rectally, e.g. in the form of suppositories,parenterally, e.g. in the form of injection solutions or suspensions orinfusion solutions, or topically, e.g. in the form of ointments, creamsor oils. Oral administration is preferred.

The production of the pharmaceutical preparations can be effected in amanner which will be familiar to any person skilled in the art bybringing the described compounds of formula I and/or theirpharmaceutically acceptable salts, optionally in combination with othertherapeutically valuable substances, into a galenical administrationform together with suitable, non-toxic, inert, therapeuticallycompatible solid or liquid carrier materials and, if desired, usualpharmaceutical adjuvants.

Suitable carrier materials are not only inorganic carrier materials, butalso organic carrier materials. Thus, for example, lactose, corn starchor derivatives thereof, talc, stearic acid or its salts can be used ascarrier materials for tablets, coated tablets, dragees and hard gelatinecapsules. Suitable carrier materials for soft gelatine capsules are, forexample, vegetable oils, waxes, fats and semi-solid and liquid polyols(depending on the nature of the active ingredient no carriers might,however, be required in the case of soft gelatine capsules). Suitablecarrier materials for the production of solutions and syrups are, forexample, water, polyols, sucrose, invert sugar and the like. Suitablecarrier materials for injection solutions are, for example, water,alcohols, polyols, glycerol and vegetable oils. Suitable carriermaterials for suppositories are, for example, natural or hardened oils,waxes, fats and semi-liquid or liquid polyols. Suitable carriermaterials for topical preparations are glycerides, semi-synthetic andsynthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins,liquid fatty alcohols, sterols, polyethylene glycols and cellulosederivatives.

Usual stabilizers, preservatives, wetting and emulsifying agents,consistency-improving agents, flavour-improving agents, salts forvarying the osmotic pressure, buffer substances, solubilizers, colorantsand masking agents and antioxidants come into consideration aspharmaceutical adjuvants.

The dosage of the compounds of formula I can vary within wide limitsdepending on the disease to be controlled, the age and the individualcondition of the patient and the mode of administration, and will, ofcourse, be fitted to the individual requirements in each particularcase. For adult patients a daily dosage of about 1 to 1000 mg,especially about 1 to 300 mg, comes into consideration. Depending onseverity of the disease and the precise pharmacokinetic profile thecompound could be administered with one or several daily dosage units,e.g. in 1 to 3 dosage units.

The pharmaceutical preparations conveniently contain about 1-500 mg,preferably 1-100 mg, of a compound of formula I.

The following Examples serve to illustrate the present invention in moredetail. They are, however, not intended to limit its scope in anymanner.

EXAMPLES Example 1 and 2

Trans-(1SR,2SR)-4-Methylene-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(1) and Cis-(1SR,2RS)-4-methylene-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(2) Step 1: trans-(1SR,2SR)-4-Methylene-cyclopentane-1,2-dicarboxylicacid ethyl ester (1a)

A suspension of 20.0 g oftrans-(1SR,2SR)-4-methylene-cyclopentane-1,2-dicarboxylic acid diethylester and 36.6 g of potassium carbonate in 200 ml of MeOH was heated atreflux temperature for 2 h. The mixture was cooled to 22°, diluted with200 ml of water, the pH was adjusted to 2 using 80 ml of 25% HCl and themixture was evaporated to half of the volume. The aqueous layer wasextracted with AcOEt, the organic layer was washed with water, dried andevaporated to give 16.7 g of a crude mixture of mono and diacid.Optionally this mixture can be purified on silica using CH₂Cl₂/MeOH(19:1) to give 8.60 g of the pure title compound 1a. MS: 183.3 (M−H)⁻.

Step 2:trans-(1SR,2SR)-2-(4-Chloro-phenylcarbamoyl)-4-methylene-cyclopentanecarboxylic acid methyl ester (1b)

The crude mixture containing 1a (16.7 g) was dissolved in 500 ml ofCH₃CN and treated subsequently with 51 ml of NEt₃, 25.0 ghydroxybenzotriazole and 31.3 g ofN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride andstirring was continued at 22° C. for 30 min. The mixture was treatedwith 23.1 g of 4-chloroaniline and stirring was continued at 22° C. for16 h and at 60° C. for 5 h. The mixture was evaporated and the residuepartitioned between AcOEt and 0.1 N NaOH. The organic layer was washedwith 0.1 N NaOH, 1 N HCl and brine, dried and evaporated to give 13.7 gof the crude title compound 1b.

Step 3:trans-(1SR,2SR)-2-(4-Chloro-phenylcarbamoyl)-4-methylene-cyclopentanecarboxylic acid (1c)

The crude material 1b (13.7 g) was dissolved in 200 ml of MeOH and 20 mlof 7 N NaOH, the solution was stirred at 22° C. for 2 h and evaporated.The residue was partitioned between 0.1 N NaOH and CH₂Cl₂, the aqueouslayer was washed with CH₂Cl₂ and the aqueous layer was acidified with25% HCl, the suspension was filtered and the residue dried to give 11.0g (45% overall) of the pure title compound 1c as a pale brown solid. MS:278.3 (M−H)⁻.

Step 4: Trans-(1SR,2SR)-4-Methylene-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(1) and cis-(1SR,2RS)-4-Methylene-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(2)

To a solution of 6.0 g of 1c and 2.6 ml of 4-methylmorpholine in 60 mlof THF was added at −16° C. 3.1 ml of isobutyl chloroformate over 20min, the suspension was stirred at −16° C. for 20 min and then warmed to0° C. The mixture was diluted with 4 ml of DMF and after 10 min cooledto −16° C. The mixture was treated with a suspension of 4.82 g of1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (prepared according to C.F. Bigge et al., patent application WO 2003045912) in 40 ml of DMF andheated at 60° C. for 1 h. A further portion of 0.56 ml of isobutylchloroformate was added and stirring was continued at 22° C. for 16 h.The mixture was evaporated, the residue partitioned between 1 N HCl andCH₂Cl₂, the organic layer was washed with 1 N HCl, 1 N NaOH and brine,dried and evaporated. The brown residue was chromatographed on silica(700 g) using a gradient of CH₂Cl₂/MeOH (100:1 to 95:5) to give 3.67 g(37%) of the pure title compound 1. MS: 466.3 (M+H)⁺.

The second fraction contained 2.04 g (20%) of the pure title compound 2.MS: 466.1 (M+H)⁺.

Example 3

Trans-(1SR,2SR)-4-Oxo-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

To a solution of 2.80 g of compound 1 in 200 ml of MeOH and 65 ml ofwater was added at 22° C. 3.8 ml of a 2.5% solution of OSO₄ in t-BuOHand 3.89 g of NaIO₄ and stirring was continued at 22° C. for 1 h. Thesuspension was evaporated to a volume of ca. 50 ml and partitionedbetween AcOEt and brine. The organic layer was dried, evaporated and theresidue chromatographed on silica using a gradient of AcOEt/heptane (3:1to 5:1) to give 2.27 g (81%) of the pure title compound. MS: 468.5(M+H)⁺.

Example 4

Cis-(1SR,2RS)-4-Oxo-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Starting from 2 the title compound was prepared in 90% yield accordingto the procedure described in example 3. MS: 468.4 (M+H)⁺.

Example 5

Mixture of (3RS,5SR,6SR)- and(3SR,5SR,6SR)-1-Oxa-spiro[2.4]heptane-5,6-dicarboxylic acid5-[(4-chloro-phenyl)-amide]6-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

A suspension of 0.54 g of compound 1 (from example 1 and 2) in 20 ml ofCH₂Cl₂ was treated at 22° C. with 0.51 g of 70% m-chloroperbenzoic acidand stirring was continued for 3 h. The mixture was treated with 10 mlof a saturated aqueous solution of Na₂SO₃ and stirring was continued for30 min. The mixture was washed with 1 N NaOH and brine, the organiclayer was dried and evaporated. The residue was chromatographed onsilica (epoxide pre-adsorbed on silica) using AcOEt to give 0.41 g (73%)of the pure title compound. MS: 482.5 (M+H)⁺. The epoxide epimers(3RS,5SR,6SR)- and (3SR,5SR,6SR) can be separated using a larger amountof silica.

Example 6

Mixture of (1SR,2SR,4RS)- and(1SR,2SR,4SR)-4-Amino-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

A solution of 500 mg of the ketone from example 3 and 8.25 g of ammoniumacetate in 100 ml of MeOH was treated with 77 mg of sodiumcyanoborohydride and stirring was continued for 16 h. The solution wasevaporated, the residue partitioned between CH₂Cl₂ and 0.1 N HCl, the pHof the aqueous layer was adjusted to 9 using 1 N NaOH and extracted withCH₂Cl₂. The organic layer was washed with brine, dried and evaporated togive 60% of the title compound. MS: 569.4 (M+H)⁺.

Example 7

Mixture of (1SR,2RS,4RS)- and(1SR,2RS,4SR)-4-Amino-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Starting from the ketone from example 4, the title compound was preparedin 64% yield according to the procedure described in example 6. MS:569.5 (M+H)⁺.

Example 8

Mixture of (1SR,2SR,4RS)- and(1SR,2SR,4SR)-4-ethylamino-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}General Procedure

To a solution of 0.1 mmole of the ketone from example 3 and 0.2 mmole ofthe amine in 2.5 ml of THF was added at 0° C. AcOH until the pH was 5followed by addition of 0.11 mmole of sodium cyanoborohydride andstirring was continued at 22° C. for 16 h. The mixture was evaporatedand the residue purified by prep. HPLC(RP-18) using a gradient ofCH₃CN/H₂O (containing 0.1% of HCOOH) (20:80 to 95:5).

Starting from the ketone from example 3 and methylamine, the titlecompound was prepared in 65% yield. MS: 583.5 (M+H)⁺.

Example 9

Mixture of (1SR,2RS,4RS)- and(1SR,2RS,4SR)-ethylamino-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Starting from the ketone from example 4 and methylamine, the titlecompound was prepared in 70% yield. MS: 583.1 (M+H)⁺.

Example 10

Mixture of (1SR,2SR,4RS)- and(1SR,5R,4SR)-4-(2,2-difluoro-ethylamino)-cyclopentane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Starting from the ketone from example 3 and 2,2-difluororoethylamine,the title compound was prepared in 87% yield. MS: 533.3 (M+H)⁺.

Example 11

Mixture of (1SR,2SR,4RS)- and(1SR,5R,4SR)-4-Propylamino-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[{2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Starting from the ketone from example 3 and propylamine, the titlecompound was prepared in 67% yield. MS: 511.5 (M+H)⁺.

Example 12

Mixture of (1SR,2SR,4RS)- and(1SR,2SR,4SR)-4-Dimethylamino-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Starting from the ketone from example 3 and dimethylamine, the titlecompound was prepared in 22% yield. MS: 497.1 (M+H)⁺.

Example 13

Mixture of (1SR,2SR,4RS)- and(1SR,2SR,4SR)-4-Diethylamino-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[{2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Starting from the ketone from example 3 and diethylamine, the titlecompound was prepared in 52% yield. MS: 525.5 (M+H)⁺.

Example 14

Mixture of (1SR,2SR,4RS)- and(1SR,2SR,4SR)-4-Ethanesulfonylamino-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}General Procedure

To a solution of 0.1 mmole of the amine and 0.25 mmole ofN,N-diisopropylethylamine in 0.7 ml of CH₃CN was added at 22° C. 0.15mmole of the sulfonylchloride or methyl chloroformate orp-nitrophenylformate and stirring was continued for 1-16 h. The mixturewas evaporated and the residue chromatographed on silica usingCH₂Cl₂/MeOH (97:3).

Starting from the amine from example 6 and ethylsulfonyl chloride, thetitle compound was prepared in 61% yield. MS: 560.9 (M+H)⁺.

Example 15

Mixture of (1SR,2SR,4RS)- and(1SR,2SR,4SR)-(Methanesulfonyl-methyl-amino)-cyclopentane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Starting from the amine from example 8 and methylsulfonyl chloride, thetitle compound was prepared in 69% yield. MS: 561.3 (M+H)⁺.

Example 16

Mixture of (1SR,2RS,4RS)- and(1SR,2RS,4SR)-4-(Methanesulfonyl-methyl-amino)-cyclopentane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Starting from the amine from example 9 and methylsulfonyl chloride, thetitle compound was prepared in 74% yield. MS: 561.0 (M+H)⁺.

Example 17

Mixture of (1SR,2SR,4RS)- and(1SR,2SR,4SR)-4-(Ethanesulfonyl-methyl-amino)-cyclopentane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Starting from the amine from example 8 and ethylsulfonyl chloride, thetitle compound was prepared in 45% yield. MS: 575.0 (M+H)⁺.

Example 18

Mixture of (1SR,2SR,4RS)- and(1SR,2SR,4SR)-4-(Dimethylsulfamoyl-methyl-amino)-cyclopentane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Starting from the amine from example 8 and dimethylsulfamoyl chloride,the title compound was prepared in 78% yield. MS: 590.5 (M+H)⁺.

Example 19

Mixture of (1RS,3SR,4SR)- and(1SR,3SR,4SR)-3-(4-Chloro-phenylcarbamoyl)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopentyl}-carbamicacid methyl ester

Starting from the amine from example 6 and methyl chloroformate, thetitle compound was prepared in 96% yield. MS: 527.3 (M+H)⁺.

Example 20

(1RS,3SR,4RS)- or(1SR,3SR,4RS)-3-(4-Chloro-phenylcarbamoyl)-4-[2-fluoro-4-(2-oxo-2-pyridin-1-yl)-phenylcarbamoyl]-cyclopentyl}-carbamicacid methyl ester

Starting from the amine from example 6 and methyl chloroformate, thetitle compound was prepared in 30% yield after crystallization fromEtOH. MS: 527.0 (M+H)⁺.

Example 21

Mixture of (1SR,2SR,4RS)- and(1SR,2SR,4SR)-4-Formylamino-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[{2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Starting from the amine from example 6 and p-nitrophenylformate, thetitle compound was prepared in 77% yield. MS: 497.1 (M+H)⁺.

Example 22

Mixture of (1SR,2SR,4RS)- and(1SR,2SR,4SR)-4-Hydroxy-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

To a solution of 450 mg of the ketone from example 3 in 9 ml of THF wasadded at 22° C. 110 mg of sodium borohydride and stirring was continuedfor 1 h. The solution was quenched with 3 drops of 1 N HCl and 10 ml ofbrine and the aqueous layer was extracted with AcOEt. The organic layerwas dried, evaporated and the residue chromatographed on silica usingCH₂Cl₂/MeOH (20:1) to give 417 mg (92%) of the title compound. MS: 470.1(M+H)⁺.

Example 23

Mixture of (1SR,2RS,4RS)- and(1SR,2RS,4SR)-4-Hydroxy-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

To a suspension of 93 mg of the ketone from example 4 in 5 ml of THF wasadded at 22° C. 38 mg of sodium borohydride and stirring was continuedfor 2 h. The suspension was diluted with 1 ml of MeOH and stirring wascontinued for 15 min. The solution was evaporated and the residuepartitioned between 1 N HCl and CH₂Cl₂. The organic layer was dried,evaporated and the residue triturated with AcOEt to give 67 mg (72%) ofthe title compound. MS: 469.5 (M+H)⁺.

Example 24

Mixture of (1SR,2SR,4RS)- and(1SR,2SR,4SR)-4-Hydroxy-4-methylaminomethyl-cyclopentane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}General Procedure

A solution of 0.5 mmole of the epoxide from example 5 and 5 mmole of theamine in 10 ml of EtOH was heated in a sealed tube to 40° C. for 1-20 h.The solution was evaporated and the residue chromatographed on silicausing a gradient of CH₂Cl₂ to CH₂Cl₂/MeOH 10:1. Starting from theepoxide from example 5 and MeNH₂, the title compound was prepared in 78%yield. MS: 513.5 (M+H)⁺.

Example 25

Mixture of (1SR,2SR,4RS)- and(1SR,2SR,4SR)-4-[(2,2-Difluoro-ethylamino)-methyl]-4-hydroxy-cyclopentane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Starting from the epoxide from example 5 and CHF₂CH₂NH₂, the titlecompound was prepared in 78% yield. MS: 563.5 (M+H)⁺.

Example 26

Mixture of (1SR,2SR,4RS)- and(1SR,2SR,4SR)-4-Dimethylaminomethyl-4-hydroxy-cyclopentane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Starting from the epoxide from example 5 and Me₂NH the title compoundwas prepared in 70% yield. MS: 527.2 (M)⁺.

Example 27

Mixture of (1SR,2SR,4RS)- and(1SR,2SR,4SR)-4-Hydroxy-4-[(methanesulfonyl-methyl-amino)-methyl]-cyclopentane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}General Procedure

To a suspension of 0.1 mmole of the aminoalcohol from example 24 in 1.5ml of CH₃CN was added subsequently at 22° C. 0.3 mmole ofN-ethyldiisopropylamine and 0.3 mmole of the sulfochloride and stirringwas continued for 4 h. The mixture was evaporated and the residuepartitioned between CH₂Cl₂ and 1 N HCl. The organic layer was washedwith 1 N NaOH and brine, dried and evaporated. The residue was purifiedby prep. HPLC(RP-18) using a gradient of CH₃CN/H₂O (containing 0.1% ofHCOOH) (20:80 to 95:5). Starting from the aminoalcohol from example 24and MeSO₂Cl, the title compound was prepared in 58% yield. MS: 591.5(M)⁺.

Example 28

Mixture of (1SR,2SR,4RS)- and(1SR,2SR,4SR)-4-[(Ethanesulfonyl-methyl-amino)-methyl]-4-hydroxy-cyclopentane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Starting from the aminoalcohol from example 24 and EtSO₂Cl, the titlecompound was prepared in 69% yield. MS: 605.3 (M)⁺.

Example 29

Mixture of (1SR,2SR,4RS)- and(1SR,2SR,4SR)-4-Hydroxy-4-hydroxymethyl-cyclopentane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

To a suspension of 30 mg of the epoxide from example 5 in 0.5 ml of THFwas added at 22° C. 0.5 ml of 1M H₂SO₄ and stirring was continued for 2h. The solution was neutralized with Na₂CO₃ and evaporated. The residuewas chromatographed on a thick layer silica plate using CH₂Cl₂/MeOH(9:1) to give the title compound in 74% yield. MS: 498.3 (M−H)⁻.

Example 30

Mixture of (1SR,2SR,4RS)- and(1SR,2SR,4SR)-4-Hydroxymethyl-4-methoxy-cyclopentane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}General Procedure

To a solution of 0.1 mmole of the epoxide from example 5 in 1.5 ml ofthe alcohol was added at 0° C. 0.2 mmole BF₃.OEt₂ and stirring wascontinued at 22° C. for 2 h. The solution was evaporated and the residuechromatographed on a thick layer silica plate using CH₂Cl₂/MeOH (15:1)to give the pure product.

Starting from the epoxide from example 5 and MeOH, the title compoundwas prepared in 52% yield. MS: 514.5 (M+H)⁺.

Example 31

Mixture of (1SR,2SR,4RS)- and(1SR,2SR,4SR)-4-Ethoxy-4-hydroxymethyl-cyclopentane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Starting from the epoxide from example 5 and EtOH, the title compoundwas prepared in 34% yield. MS: 528.5 (M+H)⁺.

Example 32

Mixture of (1SR,2SR,4RS)- and(1SR,2SR,4SR)-4-Hydroxymethyl-4-propoxy-cyclopentane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Starting from the epoxide from example 5 and PrOH, the title compoundwas prepared in 52% yield. MS: 542.3 (M)⁺.

Example 33

Mixture of (2SR,3SR,5RS)- and(2SR,3SR,5SR)-6,9-Dioxa-spiro[4.5]decane-2,3-dicarboxylic acid2-[(4-chloro-phenyl)-amide]3-[{2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

To a solution of 0.2 mmole of the epoxide from example 5 in 2 ml of2-chloroethanol was added at 0° C. 0.01 mmole BF₃.OEt₂ and stirring wascontinued at 22° C. for 1 h. The solution was evaporated, the residuepartitioned between water and AcOEt and the organic layer was dried andevaporated. The residue was chromatographed on silica using a gradientof CH₂Cl₂ to

CH₂Cl₂/MeOH (30:1) to give 60 mg of the intermediate chloroalcohol. Thematerial was dissolved in 2 ml of CH₃CN, 30 mg of KI and 0.17 ml of 32%NaOH were added and the mixture was heated in a microwave apparatus to100° C. for 15 min. The mixture was evaporated and the residuepartitioned between sat. NH₄Cl and AcOEt, the organic layer was driedand evaporated. The residue was purified by prep. HPLC(RP-18) using agradient of CH₃CN/H₂O (containing 0.1% of HCOOH) (20:80 to 95:5) to give6 mg of the title compound. MS: 526.3 (M+H)⁺.

Example 34

Mixture of (1SR,2SR,4RS)- and(1SR,2SR,4SR)-4-Hydroxy-4-methyl-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

To a solution of 72 mg of the epoxide from example 5 in 0.5 ml of a 5 MLiClO₄ in Et₂O was added at 22° C. 32 μl of BH₃.NEt₃ and stirring wascontinued at 22° C. for 3 h. The solution was partitioned between waterand CH₂Cl₂ and the organic layer was dried and evaporated. The residuewas chromatographed on silica using CH₂Cl₂/MeOH (9:1) to give 26 mg(36%) of the title compound. MS: 484.5 (M+H)⁺.

Example 35

N-[(5R,2SR)-2-(4-Chloro-phenylcarbamoyl)-4-methylene-cyclopentyl]-2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-benzamideStep 1:(1RS,2RS)-2-tert-butoxycarbonylamino-4-methylene-cyclopentanecarboxylicacid methyl ester (35a)

To a solution of 2.03 gtrans-(1SR,2SR)-4-methylene-cyclopentane-1,2-dicarboxylic acid ethylester (prepared and purified according to example 1 and 2, step 1) and1.13 g of NEt₃ in 25 ml of toluene was added drop wise at 22° C. 3.03 gof diphenylphosphoryl azide and the mixture was heated at 80° C. for 30min. The mixture was diluted with 4.08 g of t-BuOH and heating wascontinued at 90° C. for 16 h. The mixture was evaporated and the residuechromatographed on silica using a gradient of CH₂Cl₂ to CH₂Cl₂/MeOH(99:1) to give 1.55 g (55%) of the title compound 35a.

Step 2:(1RS,2RS)-2-tert-Butoxycarbonylamino-4-methylene-cyclopentanecarboxylicacid (35b)

To a solution of 1.28 g of 35a in 30 ml of MeOH was added a solution of0.42 g of LiOH.H₂O in 10 ml of H₂O and stirring was continued at 50° C.for 1 h. The solution was evaporated to approximately half of thevolume, the aqueous layer was washed with Et₂O, acidified with HCl, thesuspension was filtered and the residue dried to give 1.13 g (93%) ofthe title compound 35b. MS: 242.4 (M+H)⁺.

Step 3:[(1SR,2SR)-2-(4-Chloro-phenylcarbamoyl)-4-methylene-cyclopentyl]-carbamicacid tert-butyl ester (35c)

A stirred solution of 1.085 g of 35b in 10 ml of THF was treatedsubsequently with 1.25 ml of NEt₃, 0.69 g hydroxybenzotriazole, 1.21 gof N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 0.63g of 4-chloroaniline and stirring was continued at 22° C. for 16 h. Themixture was evaporated and the residue partitioned between CH₂Cl₂ and 1N HCl. The separated organic layer consisting of a white suspension wasfiltered and the residue dried to give 1.01 g (64%) of the titlecompound 35c. MS: 351.4 (M+H)⁺.

Step 4: (1SR,2SR)-2-Amino-4-methylene-cyclopentanecarboxylic acid(4-chloro-phenyl)-amide (35d)

A solution of 0.98 g of 35c in 10 ml of CH₂Cl₂ and 1.07 ml oftrifluoroacetic acid was stirred at 22° C. for 2 h. The solution wasevaporated and the residue partitioned between H₂O and CH₂Cl₂. Theaqueous layer was treated slowly with NaHCO₃ until pH=8, the suspensionwas filtered, the residue washed with H₂O and dried to give 0.48 g (69%)of the title compound 35d. MS: 251.3 (M+H)⁺.

Step 5: 2-Fluoro-4-(2-oxo-2H-pyridin-1-yl)-benzoic acid (35e)

To a solution of 10.96 g of 4-bromo-2-fluoro-benzoic acid in 40 ml ofDMSO was added subsequently 6.67 g of 2-hydroxypyridine, 1.10 g of8-hydroxyquinoline, 1.43 g of Cu(I) I and 7.61 g of K₂CO₃ and themixture was heated to 150° C. for 18 h. The suspension was diluted withwater, filtered, the residue was washed with AcOEt, triturated withMeOH, filtered and dried to give 5.77 g of the title compound 35e. MS:234.1 (M+H)⁺.

Step 6:N-[(1SR,2SR)-2-(4-Chloro-phenylcarbamoyl)-4-methylene-cyclopentyl]-2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-benzamide(35)

Starting from 35d and 35e, the title compound was prepared in 69% yieldaccording to the procedure for example 1 and 2, step 2. MS: 466.3(M+H)⁺.

Example 36N-[(5R,2SR)-2-(4-Chloro-phenylcarbamoyl)-4-oxo-cyclopentyl]-2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-benzamide

Starting from the olefin from example 35 the title compound was preparedin 41% yield according to the procedure in example 3. MS: 468.5 (M+H)⁺.

Example 37

Mixture of (1SR,2SR,4SR)- and(1SR,2SR,4RS)—N-[4-Amino-2-(4-chloro-phenylcarbamoyl)-cyclopentyl]-2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-benzamide

Starting from the ketone of example 36, the title compound was preparedin 62% yield according to the procedure in example 6. MS: 469.5 (M+H)⁺.

Example 38

Mixture of (1SR,2SR,4SR)- and(1SR,2SR,4RS)—N-[2-(4-Chloro-phenylcarbamoyl)-4-dimethylamino-cyclopentyl]-2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-benzamide

Starting from the ketone of example 36, the title compound was preparedin 48% yield according to the procedure in example 12. MS: 497.1 (M+H)⁺.

Example 39

Mixture of (1SR,2SR,4SR)- and(1SR,2SR,4RS)—N-[2-(4-Chloro-phenylcarbamoyl)-4-ethanesulfonylamino-cyclopentyl]-2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-benzamide

Starting from the amine of example 37, the title compound was preparedin 60% yield according to the procedure in example 14. MS: 560.9 (M)⁺.

Example 40

Mixture of (1SR,2SR,4SR)- and(1SR,2SR,4RS)—N-[2-(4-Chloro-phenylcarbamoyl)-4-hydroxy-cyclopentyl]-2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-benzamide

Starting from the ketone of example 36, the title compound was preparedin 47% yield according to the procedure in example 22. MS: 470.5 (M+H)⁺.

Example 41 and 42

(1S,2S)-4-Methylene-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(41) and (1R,2S)-4-Methylene-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(42) Step 1: (1S,2S)-4-Methylene-cyclopentane-1,2-dicarboxylic aciddiethyl ester (41a)

An emulsion of 1.1 g racemictrans-4-Methylene-cyclopentane-1,2-dicarboxylic acid diethyl ester(Merck 8.14188.0010) in an aqueous buffer (potassium phosphate 5 mM,NaCl 0.1 M) was adjusted to pH 7.0. Under stirring at 7° C. thehydrolysis was performed with 14 mg lipase PN from Phycomyces nitens[Wako Chemicals GmbH Nissanstrasse 2 D-41468 Neuss Germany; catalog#122-02651] under pH control (pH-stat, 1M NaOH). After consumption of2.4 ml 1 M NaOH solution within 24 h the reaction mixture was extractedtwice with 250 ml t-butyl methyl ether. The organic phase wassubsequently washed with 250 ml saturated sodium bicarbonate and 250 mlsaturated NaCl solution. Evaporation and drying in vacuo overnightyielded 0.49 g of the title compound 41a. MS: 226.0 (M)⁺; chiral GC:ee >99% (BGB-175, 30m×0.25 mm; H₂, 120 kPa, Split 1/20; 100-180° C., 2°C./min; Inj.-T.: 200° C.; Dect.-T.: 220° C.).

Step 2: (1S,2S)-4-Methylene-cyclopentane-1,2-dicarboxylic acid monoethylester (41b)

An emulsion of 1.7 g 41a in an aqueous buffer (potassium phosphate 3 mM,NaCl 0.1 M) was adjusted to pH 7.5. Under stirring at room temperaturethe hydrolysis was performed with 15 mg lipase OF from Candida rugosaunder pH control (pH-static, 1M NaOH). After consumption of 6.5 ml 1MNaOH solution and 7 h the reaction mixture was washed with 50 ml t-butylmethyl ether. The aqueous layer was adjusted to pH 2.0 (conc. HCl) andwas extracted with 85 ml ethyl acetate. Drying over sodium sulfate,evaporation and drying overnight on a high vacuum yielded 1.28 g of thetitle compound 41b. MS: 197.2 (M−H)⁻; chiral GC: ee 99.4%.

Step 3:(1S,2S)-2-(4-Chloro-phenylcarbamoyl)-4-methylene-cyclopentanecarboxylicacid ethyl ester (41c)

Starting from 41b, the title compound was prepared in 73% yieldaccording to the procedure for example 1 and 2, step 2. MS: 308.3(M+H)⁺.

Step 4:(1S,2S)-2-(4-Chloro-phenylcarbamoyl)-4-methylene-cyclopentanecarboxylicacid (41d)

Starting from 41c, the title compound was prepared in 100% yieldaccording to the procedure for example 1 and 2, step 3. MS: 278.3(M−H)⁻.

Step 5: (1S,2S)-4-Methylene-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(41) and (1R,2S)-4-Methylene-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(42)

Starting from 41d, the title compound 41 was prepared according to theprocedure for example 1 and 2, step 4. MS: 466.1 (M+H)⁺.

The second fraction afforded the title compound 42. MS: 466.3 (M+H)⁺.

Example 43

(1S,2S)-4-Oxo-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Starting from 41, the title compound 43 was prepared in quantitativeyield according to the procedure for example 3. MS: 468.5 (M+H)⁺.

Example 44 and 45

(3R or 3S,5S,6S)-1-Oxa-spiro[2.4]heptane-5,6-dicarboxylic acid5-[(4-chloro-phenyl)-amide]6-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(44) and (3S or 3R,5S,6S)-1-Oxa-spiro[2.4]heptane-5,6-dicarboxylic acid5-[(4-chloro-phenyl)-amide]6-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(45)

Starting from 41, the title compounds 44 and 45 were prepared accordingto the procedure for example 5 to give in the first fraction compound44. MS: 482.5 (M+H)⁺. The second fraction afforded compound 45. MS:482.5 (M+H)⁺.

Example 46

(1S,2S,4R)- or(1S,2S,4S)-4-Hydroxymethyl-4-methoxy-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Starting from 44, the title compound was prepared according to theprocedure for example 30. MS: 514.5 (M+H)⁺.

Example 47

(1S,2S,4S)- or(1S,2S,4R)-4-Hydroxymethyl-4-methoxy-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Starting from 45, the title compound was prepared according to theprocedure for example 30. MS: 514.5 (M+H)⁺.

Example 48

(5S,6S)-Spiro[2.4]heptane-5,6-dicarboxylic acid(4-chloro-phenyl)-amide[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide

To a solution of 0.69 ml of a 1M diethylzinc solution in hexane and 2 mlof CH₂Cl₂ was subsequently added at 0° C. 54 μl of CF₃COOH and 10 minlater 55 μl of CH₂I₂. After a further 10 min at 0° C., a solution of 80mg of 41 in 1 ml of CH₂Cl₂ was added and stirring was continued at 20°C. for 20 h. The mixture was partitioned between AcOEt and 1 N HCl, theorganic layer was washed with brine, dried and evaporated. The residuewas chromatographed on silica using CH₂Cl₂/MeOH (50:1) to give the titlecompound in 52% yield. MS: 480.5 (M+H)⁺.

Example 49

(1S,2S,4S)-4-Fluoro-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}Step 1:(1S,2S)-2-(4-Chloro-phenylcarbamoyl)-4-oxo-cyclopentanecarboxylic acidethyl ester (49a)

Starting from 41c, the title compound was prepared in quantitative yieldaccording to the procedure for example 3. MS: 310.0 (M+H)⁺.

Step 2: (1S,2S,4R)- and(1S,2S,4S)-2-(4-Chloro-phenylcarbamoyl)-4-hydroxy-cyclopentanecarboxylicacid ethyl ester (49b and 49c)

Starting from 49a, the title compounds were prepared according to theprocedure for example 22. Separation of the epimers 49b and 49c wasaccomplished by chromatography on silica using CH₂Cl₂/MeOH (100:1). Thefirst fraction afforded 49b in 49% yield. MS: 312.3 (M+H)⁺. The secondfraction gave 49c in 29% yield. MS: 312.3 (M+H)⁺.

Step 3:(1S,2S,4S)-2-(4-Chloro-phenylcarbamoyl)-4-fluoro-cyclopentanecarboxylicacid ethyl ester (49d)

To a solution of 100 mg of 49b in 2 ml of CH₂Cl₂ was added at −60° C.0.13 ml of a 50% solution of bis-(2-methoxyethyl)-aminosulfurtrifluoride in THF and stirring was continued at −60° C. for 30 min. Thesolution was warmed to 20° C., washed with saturated aqueous NaHCO₃ andwater, the organic layer was dried and evaporated. The residue waschromatographed on silica using heptane/AcOEt (6:1) to give the titlecompound in 70% yield. MS: 314.0 (M+H)⁺.

Step 4:(1S,2S,4S)-2-(4-Chloro-phenylcarbamoyl)-4-fluoro-cyclopentanecarboxylicacid (49e)

Starting from 49d, the title compound was prepared in quantitative yieldaccording to the procedure for example 1 and 2, step 3. MS: 284.1(M−H)⁻.

Step 5: (1S,2S,4S)-4-Fluoro-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(49)

Starting from 49e, the title compound was prepared in 50% yieldaccording to the procedure for example 1 and 2, step 4. MS: 472.4(M+H)⁺.

Example 50

(1S,2S)-4,4-Difluoro-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}Step 1:(1S,2S)-2-(4-Chloro-phenylcarbamoyl)-4,4-difluoro-cyclopentanecarboxylicacid (50a)

To a solution of 52 mg of 49a in 1 ml of CH₂Cl₂ was added at 0° C. 0.40ml of a 50% solution of bis-(2-methoxyethyl)-aminosulfur trifluoride inTHF and stirring was continued at 20° C. for 30 min. The solution waswashed with saturated aqueous NaHCO₃ and water, the organic layer wasdried and evaporated. The residue was chromatographed on silica usingheptane/AcOEt (7:1) to give the title compound in 31% yield. MS: 330.1(M−H)⁻.

Step 2:(1S,2S)-2-(4-Chloro-phenylcarbamoyl)-4,4-difluoro-cyclopentanecarboxylicacid (50b)

Starting from 50a, the title compound was prepared in quantitative yieldaccording to the procedure for example 1 and 2, step 3. MS: 302.0(M−H)⁻.

Step 3: (1S,2S)-4,4-Difluoro-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(50c)

Starting from 50b, the title compound was prepared in 50% yieldaccording to the procedure for example 1 and 2, step 4. MS: 488.0(M−H)⁻.

Example 51 (1S,2S,4R)-4-Hydroxy-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

A suspension of 262 mg of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one(prepared according to C. F. Bigge et al., patent application WO2003045912) in 10 ml of toluene was treated at 20° C. with 0.64 ml of a2 M AlMe₃ in heptane and stirring was continued for 1 h. 100 mg of 49bwas added and the solution was stirred at reflux temperature for 1 h.The mixture was cooled to 20° C. and partitioned between 1 N HCl andAcOEt. The organic layer was washed with water, dried and evaporated.The residue was chromatographed on silica using CH₂Cl₂/MeOH (25:1) togive the title product in 73% yield. 470.5 (M+H)⁺. The relative andabsolute configuration was determined by an X-ray analysis of 51complexed with factor Xa.

Example 52

(1S,2S,4S)-4-Hydroxy-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Starting from 49c, the title compound was prepared according to theprocedure for example 51. MS: 470.4 (M+H)⁺.

Example 53

(1S,2S,4S)-4-Methoxy-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}Step 1:(1S,2S,4S)-2-(4-Chloro-phenylcarbamoyl)-4-methoxy-cyclopentanecarboxylicacid ethyl ester (53a)

A mixture of 50 mg of 49c, 263 mg of Ag₂O and 229 mg of MeI in 0.5 ml ofMeCN and 0.2 ml of THF was stirred at 20° C. for 48 h. The suspensionwas filtered, the filtrate evaporated and the residue chromatographed onsilica using heptane/AcOEt (3:1) to give the title compound in 23%yield. MS: 326.1 (M+H)⁺.

Step 2: (1S,2S,4S)-4-Methoxy-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(53)

Starting from 53a, the title compound was prepared according to theprocedure for example 51. MS: 482.0 (M−H)⁻.

Example 54

(1S,2S)-4-Methylene-cyclopentane-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}Step 1:(1S,2S)-2-[2-Fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-4-methylene-cyclopentanecarboxylicacid ethyl ester (54a)

To a solution of 1.0 g of 41b in 10 ml of THF and 0.61 ml ofN-methylmorpholine was added at −12° C. 0.72 ml of isobutylchloroformate and stirring was continued at −15° C. for 30 min and at20° C. for 1 h. The suspension obtained was added to a hot (60° C.)solution of 1.13 g of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one(prepared according to C. F. Bigge et al., patent application WO2003045912) in 8 ml of DMF and stirring was continued at 60° C. for 1 h.The reaction mixture was evaporated and the residue partitioned between1 N HCl and AcOEt, the organic layer was washed with HCl and brine,dried and evaporated. The residue was chromatographed on silica usingheptane/AcOEt (1:2) to give 1.28 g of the title compound 54a. MS: 385.0(M+H)⁺.

Step 2: (1S,2S)-4-Methylene-cyclopentane-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

A suspension of 69 mg of 2-amino-5-chloro-pyridine in 2 ml of toluenewas treated at 20° C. with 0.26 ml of a 2 M AlMe₃ in heptane andstirring was continued for 1 h. 50 mg of 54a was added and the solutionwas stirred at reflux temperature for 2 h. The mixture was cooled to 20°C. and partitioned between 1 N HCl and AcOEt. The organic layer waswashed with water, dried and evaporated. The residue was chromatographedon a thick layer silica plate using CH₂Cl₂/MeOH (9:1) to give the titleproduct in 79% yield. MS: 467.1 (M+H)⁺.

Example 55

(1S,2S)-4-Methylene-cyclopentane-1,2-dicarboxylic acid1-[(6-chloro-pyridin-3-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Starting from 54a and 5-amino-2-chloropyridine, the title compound wasprepared in 29% yield according to the procedure for example 54, step 2.MS: 467.2 (M+H)⁺.

Example 56

(1S,2S)-4-Methylene-cyclopentane-1,2-dicarboxylic acid1-[(5-chloro-pyrimidin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Starting from 54a and 2-amino-5-chloropyrimidine, the title compound wasprepared in 6% yield according to the procedure for example 54, step 2.MS: 468.0 (M+H)⁺.

Example 57

(1S,2S)-4-Methylene-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-3-fluoro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Starting from 54a and 4-chloro-3-fluoroaniline, the title compound wasprepared in 28% yield according to the procedure for example 54, step 2.MS: 481.9 (M−H)⁻.

Example 58

(1S,2S)-4-Methylene-cyclopentane-1,2-dicarboxylic acid1-[(3-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Starting from 54a and 3-chloroaniline, the title compound was preparedin 58% yield according to the procedure for example 54, step 2. MS:466.1 (M+H)⁺.

Example 59

(1S,2S)-4-Methylene-cyclopentane-1,2-dicarboxylic acid1-[{2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}2-[(H-indol-6-yl)-amide]

Starting from 54a and 6-aminoindole, the title compound was prepared in25% yield according to the procedure for example 54, step 2. MS: 471.3(M+H)⁺.

Example 60

(1S,2S)-4-Methylene-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Starting from 41c and 1-(4-Amino-phenyl)-1H-pyridin-2-one (preparedaccording to C. F. Bigge et al., patent application WO 2003045912), thetitle compound was prepared in 23% yield according to the procedure forexample 51. MS: 448.0 (M+H)⁺.

Example 61 (1S,2S)-4-Methylene-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-methyl-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Starting from 41c and 1-(4-Amino-3-methyl-phenyl)-1H-pyridin-2-one(prepared according to C. F. Bigge et al., patent application WO2003045912), the title compound was prepared in 48% yield according tothe procedure for example 51. MS: 462.0 (M+H)⁺.

Example 62 (1S,2S)-4-Methylene-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyrazin-1-yl)-phenyl]-amide}

Starting from 41c and 1-(4-Amino-3-fluoro-phenyl)-1H-pyrazin-2-one(prepared according to C. F. Bigge et al., patent application WO2003045912), the title compound was prepared in 54% yield according tothe procedure for example 51. MS: 467.4 (M+H)⁺.

Example 63 (1S,2S)-4-Methylene-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(3-methyl-2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Starting from 41c and1-(4-Amino-3-fluoro-phenyl)-3-methyl-1H-pyridin-2-one (preparedaccording to C. F. Bigge et al., patent application WO 2003045912), thetitle compound was prepared in 59% yield according to the procedure forexample 51. MS: 480.0 (M+H)⁺.

Example 64 (1S,2S)-4-Methylene-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[5-(2-methanesulfonyl-phenyl)-pyridin-2-yl]-amide}

Starting from 41c and 5-(2-Methanesulfonyl-phenyl)-pyridin-2-ylamine(prepared according to R. A. Galemmo et al., patent applicationWO9857937), the title compound was prepared in quantitative yieldaccording to the procedure for example 51. MS: 510.0 (M+H)⁺.

Example 65 (1S,2S)-4-Methylene-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2-dimethylaminomethyl-imidazol-1-yl)-2-fluoro-phenyl]-amide}

Starting from 41c and4-(2-Dimethylaminomethyl-imidazol-1-yl)-2-fluoro-phenylamine (preparedaccording to M. L. Quan et al., patent application WO 2003047517), thetitle compound was prepared in 5% yield according to the procedure forexample 51. MS: 496.1 (M+H)⁺.

Example 66 (1S,2S)-4-Methylene-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(3-oxo-morpholin-4-yl)-phenyl]-amide}

Starting from 41c and 4-(4-Amino-3-fluoro-phenyl)-morpholin-3-one(prepared according to C. F. Bigge et al., patent application WO2003045912), the title compound was prepared in 53% yield according tothe procedure for example 51. MS: 472.1 (M+H)⁺.

Example 67 (1S,2S)-4-Methylene-cyclopentane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-2-yl)-phenyl]-amide}

Starting from 41c and4-(Tetrahydro-1,1-dioxido-2H-1,2-thiazin-2-yl)-phenylamine (preparedaccording to I. Zeid et al., Journal de la Societe Algerienne de Chimie4(2), 171, 1994), the title compound was prepared in 79% yield accordingto the procedure for example 51. MS: 488.1 (M+H)⁺.

Example 68(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid ethyl ester

Step 1: (Z)-3-(4-chloro-phenylcarbamoyl)-acrylic acid

A solution of 29.3 g (300 mmol) of maleic anhydride in 500 ml ofacetonitrile was treated portionwise with 40 g (310 mmol) of4-chloroaniline and stirred at room temperature during 24 hrs. The thickprecipitate that had formed was filtered off, washed with coldacetonitrile and dried i.v. to yield 65.7 g (97%) of the title compound.Yellow solid. MS: 226 (M+H)⁺.

Step 2: 1-(4-chloro-phenyl)-pyrrole-2,5-dione

In Analogy to the procedure given in Mhaske et al., Synthesis, 2003, p863-870: A solution of 65 g (288 mmol) of(Z)-3-(4-chloro-phenylcarbamoyl)-acrylic acid in 300 ml of benzene wastreated with 41.2 g (302 mmol) of zinc dichloride, dropwise with 90.1 ml(432 mmol) of bis(trimethylsilyl)amine and refluxed during 5 hrs. Themixture was poured into 300 ml of aqueous HCl (0.5 M). The aqueous phasewas extracted with AcOEt, the combined organic phases were washedsuccessively with saturated aqueous NaHCO₃ and brine, and finally driedover Na₂SO₄. Evaporation of the solvent gave 58 g (97%) of the titlecompound. Brown amorphous solid. MS: 208 (M+H)⁺.

Step 3: (1RS, 5SR,6R)-3-(4-chloro-phenyl)-2,4-dioxo-3-aza-bicyclo[3.1.0]hexane-6-carboxylicacid ethyl ester

A solution of 19.4 g (93 mmol) of 1-(4-chloro-phenyl)-pyrrole-2,5-dionein 120 ml of xylene was treated with 19.4 ml (187 mmol) ofethyldiazoacetate and refluxed during 12 hrs. Evaporation of the solventand chromatography on silica gel with toluene and then a gradient oftoluene/AcOEt from 95:5 to 90:10 gave 9.5 g (35%) of the title compound.Off white solid. MS: 294 (M+H)⁺.

Step 4:(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid ethyl ester

A solution of 7 g (34 mmol) of1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (prepared according to C.F. Bigge et al., patent application WO 2003045912) in 25 ml of THF wascooled to −78° C. and treated dropwise with 41 ml of a 1M lithiumbis(trimethylsilyl)amide-solution in THF and stirred for 30 min. To thissolution 9.5 g (32 mmol) of (1RS, 5SR,6R)-3-(4-chloro-phenyl)-2,4-dioxo-3-aza-bicyclo[3.1.0]hexane-6-carboxylicacid ethyl ester were added portionwise and the mixture was allowed toreach room temperature within a few hours. The mixture was then pouredinto a diluted aqueous HCl-solution (ca. 0.2 M) and extracted withAcOEt. The combined organic phases were dried with Na₂SO₄. Evaporationof the solvent and chromatography on silica gel with dichloromethane andthen with a gradient of dichloromethane/MeOH from 98:2 to 95:5 gave 4.1g (24%) of the title compound. Light brown solid. MS: 496 (M−H)⁻.

Example 69(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid

A solution of 80 mg (0.16 mmol) of(1RS,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid ethyl ester (example 68) in a mixture of 10 ml of THF and 10 ml ofa 1M aqueous LiOH-solution was stirred during 2 hrs at room temperature.The mixture was poured into 50 ml of a aqueous HCl-solution (0.5 M),extracted with AcOEt and the combined organic phases were dried overNa₂SO₄. Evaporation of the solvent gave 65 mg (86%) of the titlecompound. Off-white solid. MS: 468 (M−H)⁻.

Example 70(1S,2R,3S)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid ethyl ester

Chiral HPLC of 4 g (8.0 mmol) of(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid ethyl ester (example 68.4) on “Chiracel OD” with ethanol/heptane1:4 gave ca. 1.5 g (37%) title compound as white solid, MS: 496 (M−H)⁻along with ca. 1.5 g (37%) of the other enantiomer(1R,2S,3R)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid ethyl ester, off-white solid. MS: 496 (M−H)⁻.

Example 71(1S,2R,3S)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid

In analogy to example 69, from(1S,2R,3S)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid ethyl ester (example 70) was prepared the title compound. Whitesolid. MS: 468 (M−H)⁻.

Example 72(1RS,2SR,3SR)-3-(morpholine-4-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

A solution of 27 mg (0.057 mmol) of(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 69), 25 mg (0.29 mmol) of morpholine, 35 mg (0.34 mmol) ofN-methylmorpholine, 2 mg (0.015 mmol) of 1-hydroxybenzotriazole in 1.2ml of DMF was treated at room temperature with 17 mg (0.089 mmol) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and stirredfor 48 hours at room temperature. The mixture was poured into 5 ml of aaqueous NaOH-solution (0.5 M), extracted with AcOEt and the combinedorganic phases were dried with Na₂SO₄. Evaporation of the solvent andchromatography on silica gel with dichloromethane/MeOH 98:2 gave 28 mg(90%) of the title compound. Brown solid. MS: 537 (M−H)⁻.

Example 73(1R,2S,3S)-3-(morpholine-4-carbonyl)-cyclopropane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1S,2R,3S)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 72) was prepared the title compound. White solid. MS: 539(M+H⁺).

Example 74(1RS,2SR,3SR)-3-(3-hydroxy-pyrrolidine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)phenyl]amide}

In analogy to example 72, from(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 69) and racemic 3-hydroxypyrrolidine was prepared thetitle compound (racemic mixture of diastereomers). White solid. MS: 539(M+H)⁺.

Example 75 (1S,2S,4R)-4-Fluoro-cyclopentane-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Step 1:(1S,2S)-2-(5-Chloro-pyridin-2-ylcarbamoyl)-4-methylene-cyclopentanecar-boxylicacid ethyl ester (75a)

Starting from 41b, the title compound was prepared in 48% yieldaccording to the procedure for example 1 and 2, step 2 using2-amino-5-chloropyridine. MS: 309.1 (M+H)⁺.

Step 2:(1S,2S)-2-(5-Chloro-pyridin-2-ylcarbamoyl)-4-oxo-cyclopentanecarboxylicacid ethyl ester (75b)

Starting from 75a, the title compound was prepared in quantitative yieldaccording to the procedure for example 3. MS: 311.1 (M+H)⁺.

Step 3: (1S,2S,4R)- and(1S,2S,4S)-2-(5-Chloro-pyridin-2-ylcarbamoyl)-4-hydroxy-cyclopentanecarboxylicacid ethyl ester (75c and 75d)

Starting from 75b, the title compounds were prepared according to theprocedure for example 22. Separation of the epimers 75c and 75d wasaccomplished by chromatography on silica using diethylether. The firstfraction afforded 75c in 40% yield. MS: 313.1 (M+H)⁺. The secondfraction gave 75d in 17% yield. MS: 313.1 (M+H)⁺.

Step 4:(1S,2S,4S)-2-(5-Chloro-pyridin-2-ylcarbamoyl)-4-fluoro-cyclopentanecar-boxylicacid ethyl ester (75e)

Starting from 75c, the title compound was prepared in 81% yieldaccording to the procedure for example 49, step 3. MS: 315.3 (M+H)⁺.

Step 5:(1S,2S,4S)-2-(5-Chloro-pyridin-2-ylcarbamoyl)-4-fluoro-cyclopentanecar-boxylicacid (75f)

Starting from 75e, the title compound was prepared in 87% yieldaccording to the procedure for example 1 and 2, step 3. MS: 287.1(M+H)⁺.

Step 6: (1S,2S,4R)-4-Fluoro-cyclopentane-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(75 g)

Starting from 75f, the title compound was prepared in 45% yieldaccording to the procedure for example 1 and 2, step 4. MS: 473.0(M+H)⁺.

Example 76 (1S,2S,4S)-4-Fluoro-cyclopentane-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Step 1:(1S,2S,4R)-2-(5-Chloro-pyridin-2-ylcarbamoyl)-4-fluoro-cyclopentanecar-boxylicacid ethyl ester (76a)

Starting from 75d, the title compound was prepared in 60% yieldaccording to the procedure for example 49, step 3. MS: 315.0 (M+H)⁺.

Step 2:(1S,2S,4R)-2-(5-Chloro-pyridin-2-ylcarbamoyl)-4-fluoro-cyclopentanecar-boxylicacid (76b)

Starting from 76a, the title compound was prepared in 60% yieldaccording to the procedure for example 1 and 2, step 3. MS: 287.0(M+H)⁺.

Step 3: (1S,2S,4S)-4-Fluoro-cyclopentane-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(76c)

Starting from 76b, the title compound was prepared in 70% yieldaccording to the procedure for example 1 and 2, step 4. MS: 473.2(M+H)⁺.

Example 77 (1S,2S,4R)-4-Fluoro-cyclopentane-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-methyl-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Starting from 75f and 1-(4-amino-3-methyl-phenyl)-1H-pyridin-2-one(prepared according to C. F. Bigge et al., patent application WO2003045912), the title compound was prepared in 49% yield according tothe procedure for example 1 and 2, step 4. MS: 469.0 (M+H)⁺.

Example 78 (1S,2S,4R)-4-Fluoro-cyclopentane-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyrazin-1-yl)-phenyl]-amide}

Starting from 75f and 1-(4-amino-3-fluoro-phenyl)-1H-pyrazin-2-one(prepared according to C. F. Bigge et al., patent application WO2003045912), the title compound was prepared in 32% yield according tothe procedure for example 1 and 2, step 4. MS: 473.9 (M+H)⁺.

Example 79 (1S,2S,4R)-4-Fluoro-cyclopentane-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(3-oxo-morpholin-4-yl)-phenyl]-amide}

Starting from 75f and 4-(4-amino-3-fluoro-phenyl)-morpholin-3-one(prepared according to C. F. Bigge et al., patent application WO2003045912), the title compound was prepared in 43% yield according tothe procedure for example 1 and 2, step 4. MS: 479.0 (M+H)⁺.

Example 80 (1S,2S,4R)-4-Fluoro-cyclopentane-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[4-(3-oxo-morpholin-4-yl)-phenyl]-amide}

Starting from 75f and 4-(4-amino-phenyl)-morpholin-3-one (preparedaccording to C. Thomas et al., patent application WO 2005026135), thetitle compound was prepared in 57% yield according to the procedure forexample 1 and 2, step 4. MS: 461.0 (M+H)⁺.

Example 81 (1SR,2RS,3SR)-3-hydroxymethyl-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-[{2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

A solution of 20 mg (0.04 mmol) of(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid ethyl ester (example 68) in 0.5 ml of THF was treated with 38 mg(0.08 mmol) LiAlH₄ and stirred at RT during 1 hr. The mixture wastreated with icy water, extracted with AcOEt and the combined organicphases were dried over Na₂SO₄. Filtration, evaporation of the solventand chromatography on silica gel with dichloromethane/methanol 10:1 gave6 mg (34%) of(1SR,2RS,3SR)-3-hydroxymethyl-cyclopropane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.

Light brown semisolid. MS: 456 (M+H)⁺.

Example 82 (1SR,2SR,3RS)-cyclopropane-1,2,3-tricarboxylic acid 1-amide2-[(4-chloro-phenyl)-amide]3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 69) and ammonium chloride was prepared(1SR,2SR,3RS)-cyclopropane-1,2,3-tricarboxylic acid 1-amide2-[(4-chloro-phenyl)-amide]3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Light yellow solid. MS: 467 (M−H)⁻.

Example 83(1SR,2RS,3SR)-3-(1-hydroxy-1-methyl-ethyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

A solution of 43 mg (0.09 mmol) of(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid ethyl ester (example 68) in 1 ml of THF was cooled to −78° andtreated with 0.14 ml (0.43 mmol) of a methylmagnesiumchloride solutionin ether. The mixture was allowed to reach RT and stirred for 5 hrs. Themixture was treated with saturated aqueous NH₄Cl solution and extractedwith AcOEt. Drying of the combined organic phases over Na₂SO₄,filtration, evaporation of the solvent and chromatography on silica gelwith dichloromethane/methanol 95:5 gave 21 mg (50%) of(1SR,2RS,3SR)-3-(1-hydroxy-1-methyl-ethyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Yellow solid. MS: 484 (M+H)⁺.

Example 84(1SR,2RS,3SR)-3-(1-ethyl-1-hydroxy-propyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 83, from(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid ethyl ester (example 68) and ethylmagnesium bromide was prepared(1SR,2RS,3SR)-3-(1-ethyl-1-hydroxy-propyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Yellow solid. MS: 512 (M+H)⁺.

Example 85(1RS,2SR,3SR)-3-(piperidine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 69) and piperidine was prepared(1RS,2SR,3SR)-3-(piperidine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Light brown viscous oil. MS: 537 (M+H)⁺.

Example 86 (1RS,2SR,3SR)-cyclopropane-1,2,3-tricarboxylic acid1-[(4-chloro-phenyl)-amide]2-dimethylamide3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 69) and dimethylamine hydrochloride was prepared(1RS,2SR,3SR)-cyclopropane-1,2,3-tricarboxylic acid1-[(4-chloro-phenyl)-amide]2-dimethylamide3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}. Off-white viscousoil. MS: 497 (M+H)⁺.

Example 87 (1RS,2SR,3SR)-cyclopropane-1,2,3-tricarboxylic acid1-[(4-chloro-phenyl)-amide]3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}2-(methyl-propyl-amide)

In analogy to example 72, from(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 69) and methylpropylamine was prepared(1RS,2SR,3SR)-cyclopropane-1,2,3-tricarboxylic acid1-[(4-chloro-phenyl)-amide]3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}2-(methyl-propyl-amide).Light yellow solid. MS: 525 (M+H)⁺.

Example 88 (1RS,2SR,3SR)-cyclopropane-1,2,3-tricarboxylic acid1-[(4-chloro-phenyl)-amide]3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}2-[(2-hydroxy-ethyl)-methyl-amide]

In analogy to example 72, from(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 69) and methylamino ethanol was prepared(1RS,2SR,3SR)-cyclopropane-1,2,3-tricarboxylic acid1-[(4-chloro-phenyl)-amide]3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}2-[(2-hydroxy-ethyl)-methyl-amide].Brown viscous oil. MS: 527 (M+H)⁺.

Example 89 (1RS,2SR,3SR)-cyclopropane-1,2,3-tricarboxylic acid1-[(4-chloro-phenyl)-amide]3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}2-[(2-methoxy-ethyl)-methyl-amide]

In analogy to example 72, from(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 69) and N-(2-methoxyethyl)methylamine was prepared(1RS,2SR,3SR)-cyclopropane-1,2,3-tricarboxylic acid1-[(4-chloro-phenyl)-amide]3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}2-[(2-methoxy-ethyl)-methyl-amide].Light yellow solid. MS: 539 (M−H)⁻.

Example 90 (1SR,2RS,3SR)-cyclopropane-1,2,3-tricarboxylic acid1-(carbamoylmethyl-methyl-amide)2-[(4-chloro-phenyl)-amide]3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 69) and (methylamino)acetamide was prepared(1SR,2RS,3SR)-cyclopropane-1,2,3-tricarboxylic acid1-(carbamoylmethyl-methyl-amide)2-[(4-chloro-phenyl)-amide]3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Brown solid. MS: 538 (M−H)⁻.

Example 91(1RS,2SR,3SR)-3-(azepane-1-carbonyl)-cyclopropane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 69) and hexamethyleneimine was prepared(1RS,2SR,3SR)-3-(azepane-1-carbonyl)-cyclopropane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Brown solid. MS: 550 (M−H)⁻.

Example 92(1RS,2SR,3SR)-3-(3-oxo-piperazine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 69) and piperazine-2-one was prepared(1RS,2SR,3SR)-3-(3-oxo-piperazine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Brown solid. MS: 552 (M+H)⁺.

Example 93(1RS,2SR,3SR)-3-(3,3-difluoro-pyrrolidine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 69) and 3,3-difluoro-pyrrolidine hydrochloride wasprepared(1RS,2SR,3SR)-3-(3,3-difluoro-pyrrolidine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Brown solid. MS: 552 (M+H)⁺.

Example 94 (1SR,2SR,3RS)-cyclopropane-1,2,3-tricarboxylic acid1-[(4-chloro-phenyl)-amide]3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}2-[(2,2,2-trifluoro-ethyl)-amide]

In analogy to example 72, from(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 69) and trifluorethylamine was prepared(1SR,2SR,3RS)-cyclopropane-1,2,3-tricarboxylic acid1-[(4-chloro-phenyl)-amide]3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}2-[(2,2,2-trifluoro-ethyl)-amide].Off-white solid. MS: 551 (M+H)⁺.

Example 95 (1RS,2SR,3SR)-cyclopropane-1,2,3-tricarboxylic acid1-[(4-chloro-phenyl)-amide]2-diethylamide3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 69) and diethylamine hydrochloride was prepared(1RS,2SR,3SR)-cyclopropane-1,2,3-tricarboxylic acid1-[(4-chloro-phenyl)-amide]2-diethylamide3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}. Off-white solid.MS: 525 (M+H)⁺.

Example 96(1RS,2SR,3SR)-3-(pyrrolidine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 69) and pyrrolidine was prepared(1RS,2SR,3SR)-3-(pyrrolidine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Light brown solid. MS: 523 (M+H)⁺.

Example 97(1RS,2SR,3SR)-3-(azetidine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 69) and azetidine was prepared(1RS,2SR,3SR)-3-(azetidine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Brown solid. MS: 509 (M+H)⁺.

Example 98 (1SR,2SR,3RS)-cyclopropane-1,2,3-tricarboxylic acid1-[(4-chloro-phenyl)-amide]2-ethylamide3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 69) and ethylamine hydrochloride was prepared(1SR,2SR,3RS)-cyclopropane-1,2,3-tricarboxylic acid1-[(4-chloro-phenyl)-amide]2-ethylamide3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}. Off-white solid.MS: 497 (M+H)⁺.

Example 99 (1SR,2SR,3RS)-cyclopropane-1,2,3-tricarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2,2-difluoro-ethyl)-amide]3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 69) and 2,2-difluoroethylamine hydrochloride was prepared(1SR,2SR,3RS)-cyclopropane-1,2,3-tricarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2,2-difluoro-ethyl)-amide]3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Off-white solid. MS: 531 (M−H)⁻.

Example 100 (1RS,2SR,3SR)-3-phenyl-cyclopropane-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Step 1:

A mixture of 100 mg (0.48 mmol) of3-phenyl-cyclopropane-cis-1,2-dicarboxylic acid

(purchased from Rarechem, cat.-No: AQ C30042), 109 mg (0.53 mmol) of1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (prepared according to C.F. Bigge et al., patent application WO 2003045912), 0.32 ml (2.9 mmol)of 4-methylmorpholine 13 mg (0.1 mmol) of 1-hydroxybenzotriazole in DMFwas treated with 139 (0.73 mmol) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and stirredduring 12 hrs at RT. The mixture was poured into 5 ml of a 0.5 M aqueousHCl-solution, extracted with AcOEt and the combined organic phases weredried over Na₂SO₄. Filtration, evaporation of the solvent gave 140 mg(74%) of(1RS,2SR,3SR)-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-3-phenyl-cyclopropanecarboxylicacid. Light yellow oil. MS: 391 (M−H)⁻.

Step 2:

A solution of 140 mg (0.36 mmol) of(1RS,2SR,3SR)-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-3-phenyl-cyclopropanecarboxylicacid in 5 ml of methanol was treated at 0° C. with ca. 0.1 ml ofthionylchloride and left to stirr overnight at RT. Evaporation of thesolvent gave 160 mg of(1RS,2SR,3SR)-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-3-phenyl-cyclopropanecarboxylicacid methylester. Light yellow oil. MS: 405 (M−H)⁻.

Step 3:

A solution of 105 mg (0.82 mml) of 2-amino-5-chloropyridine in 2.5 ml ofdioxane was treated with 0.41 ml of a 2 M AlMe₃-solution in hexane (0.82mmol) and stirred at RT during two hours. To this solution was added asolution of 85 mg (0.2 mmol) of(1RS,2SR,3SR)-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-3-phenyl-cyclopropanecarboxylicacid methylester in 2.5 ml of dioxane. The resulting mixture was stirredat 90° C. during 64 hrs, treated with 0.8 ml of water, diluted with 5 mlof dioxane and dried over Na₂SO₄. Filtration, evaporation of the solventand chromatography on silica gel with heptane/AcOEt 4:1 gave 53 mg (52%)of (1RS,2SR,3SR)-3-phenyl-cyclopropane-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Light brown crystalline. MS: 504 (M+H)⁺.

Example 101(1RS,2SR,3SR)-3-(3-hydroxy-azetidine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 69) and 3-hydroxyazetidine was prepared(1RS,2SR,3SR)-3-(3-hydroxy-azetidine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Lightbrown oil. MS: 525, (M+H)⁺.

Example 102(1RS,2SR,3SR)-3-(3-hydroxy-piperidine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 69) and 3-piperidine was prepared(1RS,2SR,3SR)-3-(3-hydroxy-piperidine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Light brown oil. MS: 553 (M+H)⁺.

Example 103 (1RS,2SR,3SR)-cyclopropane-1,2,3-tricarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2,3-dihydroxy-propyl)-methyl-amide]3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 69) and 3-methylamino-1,2-propanediol was prepared(1RS,2SR,3SR)-cyclopropane-1,2,3-tricarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2,3-dihydroxy-propyl)-methyl-amide]3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Light brown oil. MS: 557 (M+H)⁺.

Example 104(1RS,2SR,3SR)-3-(4-hydroxy-piperidine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 69) and 4-hydroxypiperidine was prepared(1RS,2SR,3SR)-3-(4-hydroxy-piperidine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Light yellow crystalline. 554 (M+H)⁺.

Example 105 (1SR,2RS,3SR)-3-phenyl-cyclopropane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 100, step 3, from 4-chloroaniline and(1RS,2SR,3SR)-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-3-phenyl-cyclopropanecarboxylicacid methylester was prepared(1SR,2RS,3SR)-3-phenyl-cyclopropane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Light brown crystalline. MS: 502 (M+H)⁺.

Example 106(1RS,2SR,3SR)-3-(4-methyl-piperazine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 69) and N-methylpiperazine was prepared(1RS,2SR,3SR)-3-(4-methyl-piperazine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Yellow oil. MS: 552 (M+H)⁺.

Example 107 (1RS,2SR,3SR)-cyclopropane-1,2,3-tricarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2-dimethylamino-ethyl)-methyl-amide]3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 69) and N,N,N′-trimethylethylenediamine was prepared(1RS,2SR,3SR)-Cyclopropane-1,2,3-tricarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2-dimethylamino-ethyl)-methyl-amide]3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Light yellow oil. MS: 554 (M)⁺.

Example 108(1RS,2SR,3RS)-3-(4-acetyl-piperazine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 69) and 1-acetylpiperazine was prepared(1RS,2SR,3RS)-3-(4-actyl-piperazine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Light brown oil. MS: 578 (M−H)⁻.

Example 109(1RS,2SR,3SR)-3-(4-dimethylamino-piperidine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 69) and 4-(dimethylamino)-piperidine dihydrochloride wasprepared(1RS,2SR,3SR)-3-(4-dimethylamino-piperidine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Light brown oil. MS: 578 (M−H)⁻.

Example 110(1RS,2SR,3SR)-3-(4-carbamoyl-piperidine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 69) and isonipecotamide was prepared(1RS,2SR,3SR)-3-(4-carbamoyl-piperidine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Light brown oil. MS: 578 (M−H)⁻.

Example 111 (1RS,2SR,3SR)-cyclopropane-1,2,3-tricarboxylic acid1-[(4-chloro-phenyl)-amide]2-(dimethylcarbamoylmethyl-methyl-amide)3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 69) and (methylamino)N,N-dimethylacetamide was prepared(1RS,2SR,3SR)-Cyclopropane-1,2,3-tricarboxylic acid1-[(4-chloro-phenyl)-amide]2-(dimethylcarbamoylmethyl-methyl-amide)3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}. Light brown oil.MS: 566 (M−H)⁻.

Example 112(1R,2S,3S)-3-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1S,2R,3S)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 71) and (R)-3-hydroxypyrrolidine was prepared(1S,2R,3S)-3-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.White crystalline. MS: 539 (M+H)⁺.

Example 113(1R,2S,3S)-3-((S)-3-hydroxy-pyrrolidine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1S,2R,3S)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 71) and (S)-3-hydroxypyrrolidine was prepared(1R,2S,3S)-3-((S)-3-hydroxy-pyrrolidine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.White crystalline. MS: 539 (M+H)⁺.

Example 114(1RS,2RS,3SR)-2-(5-chloro-pyridin-2-ylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid methyl ester

Step 1:

As solution of 10 g (100 mmol) of 1,3-dioxep-5-ene in 50 ml ofdichloromethane was treated with 300 mg (0.68 mmol) of dirhodiumtetraacetate and heated to reflux. A solution of 23.9 g ofethyldiazoacetate in 35 ml of dichloromethane was added dropwise over aperiod of 3-4 hrs and the resulting mixture was stirred at reflux during10 hrs. After cooling to RT the mixture was filtered through silica geland concentrated. The resulting yellow oil was dissolved in a 0.5 M HClsolution in EtOH and refluxed during 3 hrs. Evaporation of the solventand chromatography over silica gel with heptane/AcOEt 1:1 gave 6.7 g(38%) of (1RS,2RS,3SR) 2,3-bis-hydroxymethyl-cyclopropanecarboxylic acidethyl ester. Yellow liquid. MS: 175 (M+H)⁺.

Step 2:

A solution of 1.15 g (7 mmol) of (1R,2S,3R)2,3-bis-hydroxymethyl-cyclopropanecarboxylic acid ethyl ester in toluenewas treated with 6.4 g of MnO₂ powder and intensely stirred during 10hrs at 120°. Filtration and evaporation of the solvent gave 600 mg (53%)of (1SR, 5SR, 6SR) 2-oxo-3-oxa-bicyclo[3.1.0]hexane-6-carboxylic acidethyl ester. Yellow oil. MS: 169: (M−H)⁻.

Step 3:

A solution of 600 mg (2.9 mmol) of1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (prepared according to C.F. Bigge et al., patent application WO 2003045912) in 10 ml of THF wascooled to −78° C. and treated dropwise with 3.2 ml of a 1M lithiumbis(trimethylsilyl)amide-solution in THF and stirred for 30 min. To thissolution 500 mg (3.2 mmol) of (1SR, 5SR, 6SR)2-oxo-3-oxa-bicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester dissolvedin 5m of THF were added portionwise. The mixture was allowed to reach RTand stirred for 10 hrs. The mixture was then poured into a dilutedaqueous HCl-solution (ca. 0.2 M) and extracted with AcOEt. The combinedorganic phases were dried with Na₂SO₄. Filtration, evaporation of thesolvent gave 630 mg (57%) of (1SR, 2SR, 3RS)2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-3-hydroxymethyl-cyclopropanecarboxylicacid ethyl ester. Orange foam. MS: 373 (M−H)⁻.

Step 4:

A solution of 390 mg (1.04 mmol) of (1SR, 2SR,3RS)₂-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-3-hydroxymethyl-cyclopropanecarboxylicacid ethyl ester in 10 ml of acetone was treated at 0° C. with 390 ml ofJones reagent and stirred at RT for 2 hrs. The mixture was treated with100 mg of NaHSO₃, stirred for 15 min and filtered. Evaporation of thesolvend gave a greenish solid that was dissolved in dichloromethane,treated with 76 ul of thionylchloride and stirred at RT during 2 hrs.Evaporation of the solvent and chromatography on silica gel with AcOEtgave 136 mg (35%) of (1RS, 5SR, 6RS)3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-2,4-dioxo-3-aza-bicyclo[3.1.0]hexane-6-carboxylicacid ethyl ester. Light green crystalline. MS: 369 (M−H)⁻.

Step 5:

A solution of 27.5 mg (0.21 mmol) of 2-amino-5-chloropyridine in 1 ml ofTHF was cooled to −78° C. and treated with 0.26 ml of a 1M lithiumbis(trimethylsilyl)amide-solution in THF and stirred for 30 min. To thissolution 74.5 mg (0.20 mmol) of (1RS, 5SR,6RS)₂-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-3-hydroxymethyl-cyclopropanecarboxylicacid ethyl ester dissolved in 0.5 ml of THF were added portionwise. Themixture was allowed to reach RT, stirred for 10 hrs and treated with 1ml of methanol. Evaporation of the solvent and chormatography on silicagel with AcOEt/methanol 10:1 gave 27 mg (26%) of(1RS,2RS,3SR)-2-(5-chloro-pyridin-2-ylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid methyl ester. White crystalline. MS: 485 (M+H)⁺.

Example 115 (1S,2S,3R)-cyclopropane-1,2,3-tricarboxylic acid 1-amide2-[(4-chloro-phenyl)-amide]3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1S,2R,3S)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 71) and ammoniumchloride was prepared(1S,2S,3R)-cyclopropane-1,2,3-tricarboxylic acid 1-amide2-[(4-chloro-phenyl)-amide]3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.White solid. MS. 467 (M−H)⁻

Example 116(1S,2R,3S)-3-(azepane-1-carbonyl)-cyclopropane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1S,2R,3S)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 71) and hexyleneimine was prepared(1S,2R,3S)-3-(azepane-1-carbonyl)-cyclopropane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Light brown oil. MS: 549 (M−H)⁻.

Example 117 (1S,2R,3S)-cyclopropane-1,2,3-tricarboxylic acid1-(carbamoylmethyl-methyl-amide)2-[(4-chloro-phenyl)-amide]3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1S,2R,3S)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 71) and (methylamino)N,N-dimethylacetamide was prepared(1S,2R,3S)-cyclopropane-1,2,3-tricarboxylic acid1-(carbamoylmethyl-methyl-amide)2-[(4-chloro-phenyl)-amide]3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Off-white solid. 538 (M−H)⁻

Example 118(1RS,2SR,3SR)-2-(5-chloro-pyridin-2-ylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid

A solution of 68 mg (0.14 mmol) of (1RS, 2SR,3RS)-2-(5-chloro-pyridin-2-ylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid methyl ester (example 114, step 5) in 1.5 ml of THF was treatedwith 0.2 ml of a 1M aqueous LiOH solution, stirred at RT during 2 hrsand acidified to pH ca. 2 with aqueous HCl. Extraction with AcOEt,drying of the combined organic phases over Na₂SO₄, filtration andevaporation of the solvent gave 45 mg (68%) of(1RS,2SR,3SR)-2-(5-chloro-pyridin-2-ylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid. Light yellow crystalline. MS: 469 (M−H)⁻.

Example 119(1RS,2SR,3RS)-3-(morpholine-4-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from (1SR, 2SR,3RS)-2-(5-chloro-pyridin-2-ylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 118) and morpholine was prepared(1RS,2SR,3RS)-3-(morpholine-4-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Off-white crystalline. MS: 539 (M+H)⁺.

Example 120 (1R,2S,3S)-cyclopropane-1,2,3-tricarboxylic acid1-[(4-chloro-phenyl)-amide]2-dimethylamide3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1S,2R,3S)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 71) and dimethylamine hydrochloride was prepared(1R,2S,3S)-cyclopropane-1,2,3-tricarboxylic acid1-[(4-chloro-phenyl)-amide]2-dimethylamide3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}. Light yellowviscous oil. MS: 498 (M+H)⁺.

Example 121 (1R,2S,3S)-cyclopropane-1,2,3-tricarboxylic acid1-[(4-chloro-phenyl)-amide]3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}2-[(2-hydroxy-ethyl)-methyl-amide]

In analogy to example 72, from(1S,2R,3S)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 71) and methylaminoethanol was prepared(1R,2S,3S)-cyclopropane-1,2,3-tricarboxylic acid1-[(4-chloro-phenyl)-amide]3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}2-[(2-hydroxy-ethyl)-methyl-amide]Yellowamorphous solid. MS: 528 (M+H)⁺.

Example 122(1RS,2RS,3SR)-2-(5-chloro-pyridin-2-ylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid ethyl ester

In analogy to example 114, step 5, from (1RS, 5SR,6R)₂-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-3-hydroxymethyl-cyclopropanecarboxylicacid ethyl ester and 2-amino-5-chloropyridine but without treatment withmethanol, was prepared(1RS,2RS,3SR)-2-(5-chloro-pyridin-2-ylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid ethyl ester. Off-white crystalline. MS: 500 (M+H)⁺.

Example 123(1RS,2SR,3RS)-3-(3-hydroxy-pyrrolidine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1SR,2SR,3SR)-2-(5-chloro-pyridin-2-ylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 118) and racemic 3-hydroxypyrrolidine was prepared(1RS,2SR,3RS)-3-(3-hydroxy-pyrrolidine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Light brown oil. MS: 541 (M+H)⁺.

Example 124 (1RS,2RS,3SR)-cyclopropane-1,2,3-tricarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-dimethylamide3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1SR,2SR,3SR)-2-(5-chloro-pyridin-2-ylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 118) and dimethylamino chloride was prepared(1RS,2RS,3SR)-cyclopropane-1,2,3-tricarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-dimethylamide3-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}. Light brown oil.MS: 499 (M+H)⁺.

Example 125(1RS,2SR,3RS)-3-(azepane-1-carbonyl)-cyclopropane-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1SR,2SR,3SR)-2-(5-chloro-pyridin-2-ylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 118) and hexyleneimine was prepared(1RS,2SR,3RS)-3-(azepane-1-carbonyl)-cyclopropane-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Light brown oil. MS: 553 (M+H)⁺.

Example 126 (1RS,2RS,3SR)-cyclopropane-1,2,3-tricarboxylic acid 1-amide3-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1SR,2SR,3SR)-2-(5-chloro-pyridin-2-ylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 118) and ammonium chloride was prepared(1RS,2RS,3SR)-cyclopropane-1,2,3-tricarboxylic acid 1-amide3-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Light yellow crystalline. MS: 471 (M+H)⁺.

Example 127(1R,2S,3S)-3-(4-hydroxymethyl-piperidine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1S,2R,3S)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 71) and 4-piperidine methanol was prepared(1R,2S,3S)-3-(4-hydroxymethyl-piperidine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Lightbrown crystalline. MS:565 (M−H)⁻.

Example 128(1R,2S,3S)-3-([1,4]oxazepane-4-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1S,2R,3S)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 71) and homomorpholine was prepared(1R,2S,3S)-3-([1,4]oxazepane-4-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Light yellow solid. MS: 551 (M−H)⁻.

Example 129(1R,2S,3S)-3-(2,6-dimethyl-morpholine-4-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1S,2R,3S)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 71) and 2,6-dimethylmorpholine was prepared(1R,2S,3S)-3-(2,6-Dimethyl-morpholine-4-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Light brown solid. MS: 565 (M−H)⁻.

Example 130(1RS,2SR,3SR)-3-[3-(2,2,2-trifluoro-acetylamino)-pyrrolidine-1-carbonyl]-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 69) and 3-(trifluoracetamido)pyrrolidine was prepared(1RS,2SR,3SR)-3-[3-(2,2,2-trifluoro-acetylamino)-pyrrolidine-1-carbonyl]-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Light brown oil. MS: 632 (M−H)⁻.

Example 131(1RS,2SR,3SR)-3-(3-hydroxymethyl-piperidine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 71) and 3-piperidinemethanol was prepared(1RS,2SR,3SR)-3-(3-hydroxymethyl-piperidine-1-carbonyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Yellow oil. MS: 565 (M−H)⁻.

Example 132 (1S,2R,3S)-3-hydroxymethyl-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Step 1:

In analogy to example 100, step 3, from 4-chloro-aniline and (1S,2R,3R)2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-3-(4-methoxy-phenoxymethyl)-cyclopropanecarboxylicacidmethyl ester (example 157, step 7) was prepared (1S,2R,3S)3-(4-methoxy-benzyloxymethyl)-cyclopropane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Light yellow solid. MS: 577 (M+H)⁺.

Step 2:

A solution of 50 mg (0.086 mmol) of(1S,2R,3S)-3-(4-methoxy-benzyloxymethyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}in dichloromethane was treated with 20 mg (0.09 mmol) of2,3-dichloro-5,6-dicyano-1,4-benzoquinone and stirred at RT for 5 hrs.The mixture was poured into a diluted aqueous solution of HCl andextracted with AcOEt. Drying of the combined organic phases over Na₂SO₄,filtration, evaporation of the solvent, and chromatography on silica gelwith AcOEt gave 35 mg (89%) of (1S,2R,3S)3-hydroxymethyl-cyclopropane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Light yellow solid. MS: 458 (M+H)⁺.

Example 133(1S,2R,3S)-3-(3,3-difluoro-pyrrolidin-1-ylmethyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Step 1:

A solution of 100 mg (0.22 mmol) (1S,2R,3S)3-hydroxymethyl-cyclopropane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(example 132, step 9) in 1 ml of dichloromethane was treated with 50 ulof N,N-diisopropyl ethyl amine and 30 ul of methane sulfonylchlorid. Thesolution was stirred for 2 hrs and poured into a diluted aqueoussolution of NaOH. Extraction with AcOEt, drying of the combined organicphases over Na₂SO₄, filtration and evaporation gave 110 mg (94%)(1S,2S,3R) methanesulfonic acid2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropylmethylester. Yellow oil. MS: 535 (M+H)⁺.

Step 2:

A solution of 25 mg (0.047 mmol) of (1S,2S,3R) methanesulfonic acid2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropylmethylester in DMF was treated with 60 ul of N,N-diisopropyl ethyl amine and54 mg of 3,3-difluoropyrrolidine. The mixture was stirred at 70° during10 hrs and poured into a diluted aqueous solution of NaOH. Extractionwith AcOEt, drying of the combined organic phases over Na₂SO₄,filtration, evaporation, and chromatography on silica gel with AcOEtcontaining 1% of triethylamine gave 18 mg (71%) of(1S,2R,3S)-3-(3,3-difluoro-pyrrolidin-1-ylmethyl)-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Yellow oil. MS: 543 (M−H)⁻.

Example 134(1S,2R,3S)-3-morpholin-4-ylmethyl-cyclopropane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 133, step 2, from (1S,2S,3R) methanesulfonic acid2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropylmethylester (example 133, step 1) and morpholine was prepared(1S,2R,3S)-3-morpholin-4-ylmethyl-cyclopropane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Light yellow oil. MS: 523 (M+H)⁺.

Example 135(1S,2R,3S)-3-Pyrrolidin-1-ylmethyl-cyclopropane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 133, step 2, from (1S,2S,3R) methanesulfonic acid2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropylmethylester (example 133, step 1) and pyrrolidine was prepared(1S,2R,3S)-3-pyrrolidin-1-ylmethyl-cyclopropane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Light yellow oil. 507 (M−H)⁻.

Example 136 (1S,2R,3S)-3-Fluoromethyl-cyclopropane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 133, step 2, from (1S,2S,3R) methanesulfonic acid2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropylmethylester (example 133, step 1) and tetrabutylammonium fluoride was prepared(1S,2R,3S)-3-fluoromethyl-cyclopropane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Colorless viscous oil. MS: 456 (M−H)⁻.

Example 137(1S,2R,3S)-3-Imidazol-1-ylmethyl-cyclopropane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 133, step 2, from (1S,2S,3R) methanesulfonic acid2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropylmethylester (example 133, step 1) and imidazole was prepared(1S,2R,3S)-3-imidazol-1-ylmethyl-cyclopropane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.White solid. MS:454 (M−H)⁻.

Example 138 (1S,2R,3S)-3-cyanomethyl-cyclopropane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 133, step 2, from (1S,2S,3R) methanesulfonic acid2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropylmethylester (example 133, step 1) and sodium cyanide was prepared(1S,2R,3S)-3-cyanomethyl-cyclopropane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Light yellow oil. MS: 563 (M−H)⁻.

Example 139 (1S,2R,3S)-3-methoxymethyl-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 133, step 2, from (1S,2S,3R) methanesulfonic acid2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropylmethylester (example 133, step 1) and sodium methoxide in methanol wasprepared (1S,2R,3S)-3-Methoxymethyl-cyclopropane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Light yellow oil. 470 (M+H)⁺.

Example 140 (1SR,2RS,3RS)-3-hydroxymethyl-cyclopropane-1,2-dicarboxylicacid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

A solution of 395 mg (0.79 mmol)(1RS,2RS,3SR)-2-(5-chloro-pyridin-2-ylcarbamoyl)-3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid ethyl ester (example 122) in 10 ml of ethanol was treated with 63mg (1.7 mmol) of sodium borohydride. After stirring during 2 hrsadditional 30 mg (0.8 mmol) of sodium borohydride were added and themixture stirred at 60° for 32 hrs. The mixture was poured into asaturated aqueous solution of NaCl and extracted with AcOEt. Drying ofthe combined organic phases over Na₂SO₄, filtration, evaporation of thesolvent and chromatography on silica gel with AcOEt/methanol 10:1 gave27 mg (8%) of(1SR,2RS,3RS)-3-hydroxymethyl-cyclopropane-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Colorless oil. MS: 455 (M−H)⁻.

Example 141 (1SR,2RS)-1-cyano-cyclopropane-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Step 1:

A solution of 800 mg (6.0 mmol) of (1SR, 2RS)2-oxo-3-oxa-bicyclo[3.1.0]hexane-1-carbonitrile (obtained from cyanoacetic acid allylester by application of procedures leading to similar2-oxo-3-oxa-bicyclo[3.1.0]hexanes described by Toeke et al. Tetrahedron1993, 49, p 5133-5146 and by Burgess et al. J. Org. Chem. 1992, 57, p5931-5936) in 10 ml of acetone was treated with 5 ml of Jones reagentand stirred at RT during 5 hrs. The mixture was treated with ca 100 mgof NaHSO₃, stirred 1 hr and the precipitate removed through filtration.Drying over Na₂SO₄, filtration, and evaporation gave a greenish resinthat was dissolved in 5 ml acetonitrile, treated with excess ofthionylchloride and stirred for 2 hrs. Evaporation of the solvent gave750 mg (91%) of (1SR, 2RS)2,4-dioxo-3-oxa-bicyclo[3.1.0]hexane-1-carbonitrile. Brown solid.

Step 2:

100 mg (0.73 mmol) of (1SR, 2RS)2,4-dioxo-3-oxa-bicyclo[3.1.0]hexane-1-carbonitrile were dissolved in asolution of 223 mg (1.1 mmol) of1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (prepared according to C.F. Bigge et al., patent application WO 2003045912) in 2 ml of pyridineat 0°. The mixture was stirred at RT during 2 hrs and the solventevaporated. Addition of diluted aqueous HCl, extraction with AcOEt,drying of the combined organic phases over Na₂SO₄, filtration andevaporation of the solvent gave 130 mg (52%) of (1SR, 2RS)1-cyano-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid. Light brown semisolid. MS: 340 (M−H)⁻.

Step 3:

In analogy example 100, step 2, from (1SR, 2RS)1-cyano-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid was prepared (1SR, 2RS)1-cyano-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid methyl ester. Brown semisold. MS: 356 (M+H)⁺.

Step 4:

In analogy to example 100, step 3, from (1SR, 2RS)1-cyano-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid methyl ester and 2-amino-5-chloropyridine was prepared(1SR,2RS)-1-cyano-cyclopropane-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Off-white solid. MS: 450 (M−H)⁻.

Example 142(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(4-hydroxy-2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid ethyl ester

Step 1:

A solution of 580 mg (1.87 mmol)1-(4-amino-3-fluoro-phenyl)-4-benzyloxy-1H-pyridin-2-one (example 144,step 1) in 20 ml of MeOH was treated with 140 mg of Pd/C (10%) andhydrogenated at atmospheric pressure under vigorous stirring for 3 hrs.Filtration and evaporation of the solvent gave 398 mg (97%) of1-(4-Amino-3-fluoro-phenyl)-4-hydroxy-1H-pyridin-2-one. Light brownsolid. MS: 221 (M+H)⁺.

Step 2:

In analogy to example 68, step 4, from1-(4-amino-3-fluoro-phenyl)-4-hydroxy-1H-pyridin-2-one, 2.2 equiv. oflithium bis(trimethylsilyl)amide, and (1RS, 5SR,6RS)-3-(4-chloro-phenyl)-2,4-dioxo-3-aza-bicyclo[3.1.0]hexane-6-carboxylicacid ethyl ester was prepared(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(4-hydroxy-2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid ethyl ester. Brown solid. 512 (M−H)⁻.

Example 143(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(4-methoxy-2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid ethyl ester

A solution of 35 mg (0.07 mmol) of(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(4-hydroxy-2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid ethyl ester (example 142, step 2) in 5 ml of acetone was treatedwith 94 mg (0.6 mmol) of potassium carbonate and 8 ul (0.08 mmol) ofdimethylsulfate. The mixture was stirred 2 hrs at RT and filtered.Evaporation of the solvent and chromatography on silica gel withAcOEt/methanol 95:5 gave 5 mg (13%) of(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(4-methoxy-2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid ethyl ester. Off-white solid. 526 (M−H)⁻.

Example 144(1SR,2SR,3RS)-2-[4-(4-benzyloxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenylcarbamoyl]-3-(4-chloro-phenylcarbamoyl)-cyclopropanecarboxylicacid ethyl ester

Step 1:

1-(4-Amino-3-fluoro-phenyl)-4-benzyloxy-1H-pyridin-2-one was preparedfrom 4-benzyloxy-1H-pyridin-2-one and 4-bromo-2-fluoroaniline in analogyto the procedure described for the preparation of1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one described in C. F. Bigge etal., patent application WO 2003045912. MS: 311 (M+H)⁺.

Step 2:

In analogy to example 68, step 4, from1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one and (1RS, 5SR,6RS)-3-(4-chloro-phenyl)-2,4-dioxo-3-aza-bicyclo[3.1.0]hexane-6-carboxylicacid ethyl ester was prepared(1SR,2RS,3SR)-2-[4-(4-benzyloxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenylcarbamoyl]-3-(4-chloro-phenylcarbamoyl)-cyclopropanecarboxylicacid ethyl ester. Brown solid. 602 (M−H)⁻.

Example 145(1SR,2SR,3RS)-2-[4-(4-tert-butoxycarbonylmethoxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenylcarbamoyl]-3-(4-chloro-phenylcarbamoyl)-cyclopropanecarboxylicacid ethyl ester

In analogy to example 143, from(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(4-hydroxy-2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid ethyl ester (example 142, step 2) and tert-butylbromoacetate wasprepared(1SR,2RS,3SR)-2-[4-(4-tert-butoxycarbonylmethoxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenylcarbamoyl]-3-(4-chloro-phenylcarbamoyl)-cyclopropanecarboxylicacid ethyl ester. Colorless solid. MS: 626 (M−H).

Example 146(1SR,2SR,3RS)-2-[4-(4-carbamoylmethoxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenylcarbamoyl]-3-(4-chloro-phenylcarbamoyl)-cyclopropanecarboxylicacid ethyl ester

In analogy to example 143, from(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(4-hydroxy-2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid and 2-bromoacetamide was prepared(1SR,2RS,3SR)-2-[4-(4-carbamoylmethoxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenylcarbamoyl]-3-(4-chloro-phenylcarbamoyl)cyclopropanecarboxylicacid ethyl ester. Off-white solid. MS: 569 (M−H)⁻.

Example 147(1RS,2RS)-1-(4-chloro-phenylcarbamoyl)-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid allyl ester

Step 1:

In analogy to example 141, step 1, from (1RS,2RS)2-oxo-3-oxa-bicyclo[3.1.0]hexane-1-carboxylic acid allyl ester (obtainedfrom malonic diallylester by application of procedures leading tosimilar 2-oxo-3-oxa-bicyclo[3.1.0]hexanes described by Toeke et al.Tetrahedron 1993, 49, p 5133-5146 and by Burgess et al. J. Org. Chem.1992, 57, p 5931-5936)Jones reagent and thionylchloride was prepared(1RS,2RS) 2,4-dioxo-3-oxa-bicyclo[3.1.0]hexane-1-carboxylic acid allylester. Light red oil.

Step 2:

In analogy to example 141, step 2, from (1RS,2RS)2,4-dioxo-3-oxa-bicyclo[3.1.0]hexane-1-carboxylic acid allyl ester and4-chloroaniline was prepared (1RS,2RS)2-(4-chloro-phenylcarbamoyl)-cyclopropane-1,1-dicarboxylic acid allylester. Yellow oil. 322 (M−H)⁻.

Step 3:

A solution of 400 mg (1.23 mmol) of (1RS,2RS)2-(4-chloro-phenylcarbamoyl)-cyclopropane-1,1-dicarboxylic acid allylester in dichloromethane was treated with 1.79 ml (24.6 mmol) ofthionylchloride and stirred at RT during 1 hr. Evaporation of thesolvent gave 320 mg of (1RS,2RS)3-(4-chloro-phenyl)-2,4-dioxo-3-aza-bicyclo[3.1.0] hexane-1-carboxylicacid allyl ester. Light grey crystalline. MS: 307 (M+H)⁺.

Step 4:

In analogy to example 68, step 4, from1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (prepared according to C.F. Bigge et al., patent application WO 2003045912) and (1RS,2RS)3-(4-chloro-phenyl)-2,4-dioxo-3-aza-bicyclo[3.1.0]hexane-1-carboxylicacid allyl ester was prepared(1RS,2RS)-1-(4-chloro-phenylcarbamoyl)-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid allyl ester. Light yellow oil. MS: 508 (M−H)⁻.

Example 148 (1SR,2RS)-1-hydroxymethyl-cyclopropane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

A solution of 50 mg (0.12 mmol) of(1RS,2RS)-1-hydroxymethyl-cyclopropane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(example 147, step 4) in 1 ml of ethanol was treated with 14.2 mg (0.37mmol) of sodium borohydride and stirred at RT during 16 hrs. The mixturewas poured into a 2M aqueous solution of HCl and extracted with AcOEt.Drying of the combined organic phases, filtration and evaporation of thesolvent gave 39 mg (71%) of(1SR,2RS)-1-hydroxymethyl-cyclopropane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Light yellow oil. MS: 454 (M−H)⁻.

Example 149(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[4-(4-dimethylcarbamoylmethoxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenylcarbamoyl]-cyclopropanecarboxylicacid ethyl ester

A mixture of 23 mg (0.04 mmol) of (1SR,2RS,3SR)2-[4-(4-carboxymethoxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenylcarbamoyl]-3-(4-chloro-phenylcarbamoyl)cyclopropanecarboxylicacid ethyl ester (example 155), 5 mg (0.06 mmol) of dimethylaminehydrochloride, 1 mg of 1-hydroxybenzotriazole, and 25 ul (0.23 mmol) ofN-methylmorpholine in 2.5 ml of DMF was treated with 11 mg (0.06 mmol)of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride andstirred at RT during 10 hrs. The mixture was poured into a 2M aqueoussolution of HCl and extracted with AcOEt. Drying of the combined organicphases over Na₂SO₄, filtration, evaporation of the solvent andchromatography on silica gel with AcOEt/MeOH 10:1 gave 22 mg (95%) of(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[4-(4-dimethylcarbamoylmethoxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenylcarbamoyl]-cyclopropanecarboxylicacid ethyl ester. Light brown solid. MS: 600 (M+H)⁺.

Example 150(1S,2R,3S)-3-(4-methoxy-benzyloxymethyl)-cyclopropane-1,2-dicarboxylicacid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to examples 157, step 1-157, step 8 from cis2-butene-1,4-diol was prepared(1S,2R,3S)-3-(4-methoxy-benzyloxymethyl)-cyclopropane-1,2-dicarboxylicacid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Light yellow oil. MS: 575 (M−H)⁻.

Example 151(1SR,2RS,3SR)-3-(4-methoxy-benzyloxymethyl)-cyclopropane-1,2-dicarboxylicacid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(6-oxo-cyclohexa-2,4-dienyl)-phenyl]-amide}

Step 1:

In analogy to examples 157, step 1-157, step 3 from cis2-butene-1,4-diol was prepared diazo acetic acid cis4-(4-methoxy-benzyloxy)-but-2-enyl ester. Yellow oil.

Step 2:

In analogy of example 157, step 4, from diazo acetic acid cis4-(4-methoxy-benzyloxy)-but-2-enyl ester and dirhodiumtetraacetate wasprepared (1RS, 5SR, 6RS)6-(4-methoxy-benzyloxymethyl)-3-oxa-bicyclo[3.1.0]hexan-2-one. Yellowsemisolid. 453 (M+H)⁺.

Step 3:

In analogy to examples 157, step 5-157, step 8, from (1RS, 5SR, 6RS)6-(4-methoxy-benzyloxymethyl)-3-oxa-bicyclo[3.1.0]hexan-2-one wasprepared(1SR,2RS,3SR)-3-(4-methoxy-benzyloxymethyl)-cyclopropane-1,2-dicarboxylicacid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.White crystalline. 577 (M+H)-+.

Example 152 (1SR,2RS,3SR)-3-hydroxymethyl-cyclopropane-1,2-dicarboxylicacid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 132, step 2, from(1SR,2RS,3SR)-3-(4-methoxy-benzyloxymethyl)-cyclopropane-1,2-dicarboxylicacid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(example 151, step 3) was prepared(1SR,2RS,3SR)-3-hydroxymethyl-cyclopropane-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Light yellow oil. MS: 455 (M−H)⁻.

Example 153 (1S,2R,3S)-3-hydroxymethyl-cyclopropane-1,2-dicarboxylicacid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 132, step 2, from(1S,2R,3S)-3-(4-methoxy-benzyloxymethyl)-cyclopropane-1,2-dicarboxylicacid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(example 150) was prepared(1S,2R,3S)-3-hydroxymethyl-cyclopropane-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Light brown crystalline. MS: 455 (M−H)⁻.

Example 154 (1SR,2SR)2-(5-chloro-pyridin-2-ylcarbamoyl)-1-[2-fluoro-4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid allyl ester

Step 1:

In analogy to example 141, step 2. from (1SR,2RS)2,4-dioxo-3-oxa-bicyclo[3.1.0]hexane-1-carboxylic acid allyl ester(example 147, step 1) was prepared (1RS,2RS)2-[2-fluoro-4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-cyclopropane-1,1-dicarboxylicacid allyl ester. Off-white solid. MS: 405 (M−H)⁻.

Step 2:

In analogy to example 141, step 3, from prepared (1RS,2RS)2-[2-fluoro-4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-cyclopropane-1,1-dicarboxylicacid allyl ester was prepared (1RS, 2RS)3-[2-fluoro-4-(3-oxo-morpholin-4-yl)-phenyl]-2,4-dioxo-3-aza-bicyclo[3.1.0]hexane-1-carboxylicacid allylester. Brown solid. MS: 389 (M+H)⁺.

Step 3:

In analogy to example 68, step 4, from (1RS, 2RS)3-[2-fluoro-4-(3-oxo-morpholin-4-yl)-phenyl]-2,4-dioxo-3-aza-bicyclo[3.1.0]hexane-1-carboxylicacid allylester and 2-amino-5-chloropyridine, was prepared (1SR,2SR)2-(5-chloro-pyridin-2-ylcarbamoyl)-1-[2-fluoro-4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid allyl ester. White Solid. MS: 515 (M−H)⁻.

Example 155 (1SR,2SR,3RS)2-[4-(4-carboxymethoxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenylcarbamoyl]-3-(4-chloro-phenylcarbamoyl)-cyclopropanecarboxylicacid ethyl ester

A solution of 49 mg (0.08 mmol) of(1SR,2SR,3RS)-2-[4-(4-tert-butoxycarbonylmethoxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenylcarbamoyl]-3-(4-chloro-phenylcarbamoyl)-cyclopropanecarboxylicacid ethyl ester in 3 ml of 1,2-dichloromethane was treated with 28 ulof trifluoroacetic acid and stirred at 75° C. during 40 min. Evaporationof the solvents gave 31 mg (69%) (1SR,2SR,3RS)2-[4-(4-carboxymethoxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenylcarbamoyl]-3-(4-chloro-phenylcarbamoyl)-cyclopropanecarboxylicacid ethyl ester. Off-white solid. MS: 571 (M−H)⁻.

Example 156 (1SR,2RS)-1-Cyano-cyclopropane-1,2-dicarboxylic acid2-[(5-chloro-pyridin-2-yl)-amide]1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Step 1:

In analogy to example 157, step 5, from (1SR, 2RS)2-oxo-3-oxa-bicyclo[3.1.0]hexane-1 carbonitrile (obtained from cyanoacetic acid allylester by application of procedures leading to similar2-oxo-3-oxa-bicyclo[3.1.0]hexanes described by Toeke et al. Tetrahedron1993, 49, p 5133-5146 andby Burgess et al. J. Org. Chem. 1992, 57, p5931-5936) and 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (preparedaccording to C. F. Bigge et al., patent application WO 2003045912) wasprepared (1SR, 2RS) 1-cyano-2-hydroxymethyl-cyclopropanecarboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. Yellow solid. MS: 328(M+H)⁺.

Step 2:

In analogy to example 157, step 6, from (1SR, 2RS)1-cyano-2-hydroxymethyl-cyclopropanecarboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide and Jones reagent wasprepared (1SR, 2RS)2-cyano-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid. Yellow solid. MS: 340 (M−H)⁻.

Step 3:

In analogy to example 157, step 7, from (1SR, 2RS)2-cyano-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid and iodomethane was prepared (1SR, 2RS)2-cyano-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid methyl ester. Yellow solid. MS: 354 (M−H)⁻.

Step 4:

In analogy to example 100, step 3, from 2-amino-5-chloropyridine and(1SR, 2RS)2-cyano-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid methyl ester was prepared (1SR,2RS)-1-cyano-cyclopropane-1,2-dicarboxylic acid2-[(5-chloro-pyridin-2-yl)-amide]1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Colorless foam. MS: 452 (M+H)⁺.

Example 157(1S,2R,3R)-3-(4-methoxy-benzyloxymethyl)-cyclopropane-1,2-dicarboxylicacid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Step 1:

A solution of 11.8 g (133.4 mmol) of trans 2-butene-1,4-diol in 100 mlof DMF was treated with 6.4 g (147 mmol) of sodium hydride dispersion onoil (55%), stirred at 0° C. for 45 min., and treated dropwise with 25.1g (160 mmol) of 4-methoxybenzylchloride. The mixture was stirred during5 hrs at RT and then poured into a saturated aqueous solution of NaCl.Extraction with AcOEt, drying of the combined organic phases overNa₂SO₄, filtration, evaporation of the solvent and chromatography onsilica gel with heptane/AcOEt 9:1 gave 5.7 g (21%) of trans4-(4-methoxy-benzyloxy)-but-2-en-1-ol. Light yellow oil. MS: 207 (M−H)⁻.

Step 2:

A solution of 4.7 g (22.6 mmol) 4-(4-methoxy-benzyloxy)-but-2-en-1-ol in100 ml THF was treated with 90 mg (1.13 mmol) of sodium acetate andheated to reflux. To this mixture were added dropwise 1.9 ml (24.8 mmol)of diketene and refluxing was continued for 10 hrs. After cooling to RTthe solvent was partly evaporated and the mixture poured into asaturated aqueous solution of NaCl. Extraction with AcOEt, drying of thecombined organic phases over Na₂SO₄, filtration, evaporation of thesolvent chromatography on silica gel with heptane/AcOEt 2: gave 4.29 g(65%) of trans 3-oxo-butyric acid 4-(4-methoxy-benzyloxy)-but-2-enylester. Light yellow oil. MS: 291 (M−H)⁻.

Step 3:

A solution of 4.29 g (14.7 mmol) of trans 3-oxo-butyric acid4-(4-methoxy-benzyloxy)-but-2-enyl ester in 150 ml of acetonitrile wastreated with 3.27 ml (19.1 mmol) N,N-ethyl diispropylamine and thenwithin 30 min. with a solution of 4.58 g (19.1 mmol) of4-acetamidobenzenesulfonyl azide in 25 ml of acetonitrile. The mixturewas stirred at RT during 2.5 hrs and treated with 44 ml of a 1M aqueousLiOH solution. Stirring was continued for 10 hrs and the mixture pouredinto a saturated aqueous NaCl solution. Extraction with Et₂O/AcOEt 2:1,drying of the combined organic phases over Na₂SO₄, filtration,evaporation of the solvent and chromatography on silica gel withheptane/AcOEt 2:1 gave 2.87 g (70%) of diazo-acetic acid trans4-(4-methoxy-benzyloxy)-but-2-enyl ester. Yellow oil.

Step 4:

To a solution of 1 g (3.6 mmol) of diazo-acetic acid4-(4-methoxy-benzyloxy)-but-2-enyl ester in 50 ml dichloromethane underreflux were added within 8 hrs of 25 mg (0.03 mmol) of R^(h2) (5S-MEPY)₄(Doyle dirhodium catalyst from Acros, CAS: 132435-65-5) dissolved in 100ml of dichloromethane. Refluxing for another 20 hrs, evaporation of thesolvent and chromatography on silica gel with heptane/AcOEt gave 850 mg(96%, >92% ee) of (1R,5S,6S)6-(4-methoxy-benzyloxymethyl)-3-oxa-bicyclo[3.1.0]hexan-2-one. Colorlessoil. MS: 247 (M−H)⁻.

Step 5:

A solution of 850 mg (3.4 mmol) of1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (prepared according to C.F. Bigge et al., patent application WO 2003045912) in 80 ml of THF wascooled to −78° C., treated dropwise with 4.8 ml of a 1M lithiumbis(trimethylsilyl)amide-solution in THF and stirred for 30 min at 78°C. To this solution were added 839 mg (4.8 mmol) of (1R, 5S, 6S)6-(4-methoxy-benzyloxymethyl)-3-oxa-bicyclo[3.1.0]hexan-2-one dissolvedin 5 ml of THF. Stirring was continued at −78° C. for 1 hr and then for3 hrs at RT. Pouring of the mixture into a 2M aqueous solution of HCl,extraction with AcOEt, drying of the combined organic phases overNa₂SO₄, filtration and evaporation of the solvent gave 1.2 g (77%) of(1S,2S,3S)2-hydroxymethyl-3-(4-methoxy-benzyloxymethyl)-cyclopropanecarboxylicacid [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. Yellowsemisolid. 453 (M+H)⁺.

Step 6:

A solution of 100 mg (0.22 mmol) of (1S,2S,3S)2-hydroxymethyl-3-(4-methoxy-benzyloxymethyl)-cyclopropanecarboxylicacid [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide in 5 ml ofacetone was cooled to 0° and treated dropwise with 1 ml of Jonesreagent. After stirring during 2 hrs at RT the mixture was treated with50 mg of NaHSO₃ and the solution separated from the green precipitate.Drying of the solution over Na₂SO₄, filtration, and evaporation of thesolvent gave 90 mg (90%) (1S,2R,3R)2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-3-(4-methoxy-phenoxymethyl)-cyclopropanecarboxylicacid. Greenish solid. MS: 451 (M−H)⁻.

Step 7:

A solution of 90 mg (0.19 mmol) of (1S,2R,3R)2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-3-(4-methoxy-phenoxymethyl)-cyclopropanecarboxylicacid in 3 ml of DMF was treated with 100 mg of K₂CO₃ and 0.5 ml ml ofiodomethane. The mixture was stirred for 3 hrs and poured into a dilutedaqueous solution of NaOH. Extraction with AcOEt, drying of the combinedorganic phases over Na₂SO₄, filtration and evaprotation of the solventgave 90 mg (97%) of (1S,2R,3R)2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-3-(4-methoxy-phenoxymethyl)-cyclopropanecarboxylicacidmethyl ester. Yellow oil. MS: 467 (M+H)⁺.

Step 8:

In analogy to example 100, step 3, from 2-amino-5-chloropyridine and(1S,2R,3R)2-[4-(acryloyl-propenyl-amino)-2-fluoro-phenylcarbamoyl]-3-(4-methoxy-benzyloxymethyl)cyclopropanecarboxylicacid methyl ester was prepared(1S,2R,3R)-3-(4-methoxy-benzyloxymethyl)-cyclopropane-1,2-dicarboxylicacid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Colorless foam. MS: 577 (M+H)-+.

Example 158 (1SR,2RS,3RS)-3-methoxymethyl-cyclopropane-1,2-dicarboxylicacid1-{[4-(4-carbamoylmethoxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}2-[(4-chloro-phenyl)-amide]

In analogy to example 143, from(1SR,2RS,3RS)-3-methoxymethyl-cyclopropane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(4-hydroxy-2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(example 161) 2-bromoacetamide was prepared(1SR,2RS,3RS)-3-methoxymethyl-cyclopropane-1,2-dicarboxylic acid1-{[4-(4-carbamoylmethoxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}2-[(4-chloro-phenyl)-amide].Light yellow solid. MS: 543 (M+H)⁺.

Example 159 (1SR,2RS,3RS)-3-hydroxymethyl-cyclopropane-1,2-dicarboxylicacid1-{[4-(4-benzyloxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}2-[(4-chloro-phenyl)-amide]

In analogy example 140, from(1SR,2RS,3SR)-2-[4-(4-benzyloxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenylcarbamoyl]-3-(4-chloro-phenylcarbamoyl)-cyclopropanecarboxylicacid ethyl ester (example 144) was prepared(1SR,2RS,3RS)-3-hydroxymethyl-cyclopropane-1,2-dicarboxylic acid1-{[4-(4-benzyloxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}2-[(4-chloro-phenyl)-amide].Yellow solid. MS: 562 (M+H)⁺.

Example 160 (1SR,2RS,3SR)-3-methoxymethyl-cyclopropane-1,2-dicarboxylicacid1-{[4-(4-benzyloxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}2-[(4-chloro-phenyl)-amide]

Step 1:

In analogy to example 133, step 1, from(1SR,2RS,3SR)-3-hydroxymethyl-cyclopropane-1,2-dicarboxylic acid1-{[4-(4-benzyloxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}2-[(4-chloro-phenyl)-amide](example 159) was prepared (1SR,2RS,3SR)-methanesulfonic acid2-[4-(4-benzyloxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenylcarbamoyl]-3-(5-chloro-pyridin-2-ylcarbamoyl)-cyclopropylmethylester. Yellow oil. MS: 642 (M+H)⁺.

Step 2:

In analogy to example 133, step 2, from (1SR,2RS,3SR)-methanesulfonicacid2-[4-(4-benzyloxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenylcarbamoyl]-3-(5-chloro-pyridin-2-ylcarbamoyl)-cyclopropylmethylester and sodium methoxide in methanol, was prepared(1SR,2RS,3SR)-3-methoxymethyl-cyclopropane-1,2-dicarboxylic acid1-{[4-(4-benzyloxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}2-[(4-chloro-phenyl)-amide].Brown solid. MS: 577 (M+H)⁺.

Example 161 (1SR,2RS,3SR)-3-methoxymethyl-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(4-hydroxy-2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

A solution of 100 mg (0.17 mmol) of(1SR,2RS,3SR)-3-methoxymethyl-cyclopropane-1,2-dicarboxylic acid1-{[4-(4-benzyloxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}2-[(4-chloro-phenyl)-amide](example 160, step 2) in 10 ml of methanol was treated with 43 mg ofPd/C (10%) and hydrogenated at atmospheric pressure during 30 min.Filtration and evaporation of the solvent gave 70 mg (80%) of(1SR,2RS,3SR)-3-methoxymethyl-cyclopropane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(4-hydroxy-2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Colorless solid. MS:484 (M−H)⁻.

Example 162[1-(4-{[(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-methoxymethyl-cyclopropanecarbonyl]-amino}-3-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridin-4-yloxy]-aceticacid tert-butyl ester

In analogy to example 143, from(1SR,2RS,3SR)-3-methoxymethyl-cyclopropane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(4-hydroxy-2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(example 162) and tert-butylbromoacetate wasprepared[1-(4-{[(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-methoxymethyl-cyclopropanecarbonyl]-amino}-3-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridin-4-yloxy]-aceticacid tert-butyl ester. Colorless solid. MS: 600 (M+H)⁺.

Example 163[1-(4-{[(5R,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-methoxymethyl-cyclopropanecarbonyl]-amino}-3-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridin-4-yloxy]-aceticacid

In analogy to example 155, from[1-(4-{[(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-methoxymethyl-cyclopropanecarbonyl]-amino}-3-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridin-4-yloxy]-aceticacid tert-butyl ester (example 162) wasprepared[1-(4-{[(1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-methoxymethyl-cyclopropanecarbonyl]-amino}-3-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridin-4-yloxy]-aceticacid. Brown solid. MS: 544 (M+H)⁺.

Example 164 (1SR,2RS,3SR)-3-methoxymethyl-cyclopropane-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[4-(4-dimethylcarbamoylmethoxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}

In analogy to example 149, from[1-(4-{[(1SR,2RS,3SR)-2-(4-Chloro-phenylcarbamoyl)-3-methoxymethyl-cyclopropanecarbonyl]-amino}-3-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridin-4-yloxy]-aceticacid (example 163) was prepared(1SR,2RS,3SR)-3-methoxymethyl-cyclopropane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(4-dimethylcarbamoylmethoxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}.White solid. MS: 571 (M+H)⁺.

Example 165(1RS,2RS)-2-(4-chloro-phenylcarbamoyl)-1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid

Step 1:

In analogy to example 141, step 2, from (1RS,2RS)2,4-dioxo-3-oxa-bicyclo[3.1.0]hexane-1-carboxylic acid allyl ester(example 147, step 3) and 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one(prepared according to C. F. Bigge et al., patent application WO2003045912) was prepared (1RS,2RS)2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropane-1,1-dicarboxylicacid allyl ester. Light brown crystalline. MS: 401 (M+H)⁺.

Step 2:

In analogy to example 147, step 3, from (1RS,2RS)2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropane-1,1-dicarboxylicacid allyl ester, was prepared (1RS,2RS)3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-2,4-dioxo-3-aza-bicyclo[3.1.0]hexane-1-carboxylicacid allyl ester. Light yellow crystalline. MS: 383 (M+H)⁺.

Step 3:

A solution of 1.13 g (2.96 mmol) of (1RS,2RS)3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-2,4-dioxo-3-aza-bicyclo[3.1.0]hexane-1-carboxylicacid allyl ester in 30 ml of dichloromethane/THF 1:1 was treated with257 ul (2.96 mmol) of morpholine and 103 mg (0.09 mmol) ofpalladiumtetrakis(triphenylphosphine) and stirred 1.5 hrs at RT. Themixture was poured into a ca. 2M aqueous solution of sodium bicarbonateand extracted with ether. The aqueous phase was acidified with aqueousHCl to a pH of ca. 1 and extracted with AcOEt. Drying of the combinedorganic phases over Na₂SO₄, filtration and evaporation of the solventgave 823 mg (81%) of (1RS,2RS)3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-2,4-dioxo-3-aza-bicyclo[3.1.0]hexane-1-carboxylicacid. White crystalline. MS: 343 (M+H)⁺.

Step 4:

A solution of 223 mg (1.75 mmol) of 4-chloroaniline in 10 ml of THF wascooled to −78° C. and treated dropwise with 1.75 ml of a 1M lithiumbis(trimethylsilyl)amide-solution in THF and stirred for 30 min. To thissolution 200 mg (0.58 mmol) of (1RS,2RS)3-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-2,4-dioxo-3-aza-bicyclo[3.1.0]hexane-1-carboxylicacid were added portionwise and the mixture was allowed to reach RTwithin a few hours. The mixture was then poured into a ca 2M aqueoussolution of sodium bicarbonate and extracted with ether. The aqueousphase was acidified with aqueous HCl to a pH of ca. 1 and extracted withAcOEt. The combined organic phases were dried with Na₂SO₄. Filtrationand evaporation of the solvent gave a 58 mg (77%) of(1RS,2RS)-2-(4-chloro-phenylcarbamoyl)-1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid. Light yellow crystalline. MS: 468 (M−H)⁻.

Example 166 (1RS,2RS)-cyclopropane-1,1,2-tricarboxylic acid2-[(4-chloro-phenyl)-amide]1-dimethylamide1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1RS,2RS)-2-(4-chloro-phenylcarbamoyl)-1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 165) and dimethyl amine hydrochloride was prepared(1RS,2RS)-cyclopropane-1,1,2-tricarboxylic acid2-[(4-chloro-phenyl)-amide]1-dimethylamide1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}. Light brown oil.MS: 497 (M+H)⁺.

Example 167(1RS,2RS)-1-(pyrrolidine-1-carbonyl)-cyclopropane-1,2-dicarboxylic acid2-[(4-chloro-phenyl)-amide]1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1RS,2RS)-2-(4-chloro-phenylcarbamoyl)-1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 165) and pyrrolidine was prepared (1RS,2RS)1-(pyrrolidine-1-carbonyl)-cyclopropane-1,2-dicarboxylic acid2-[(4-chloro-phenyl)-amide]1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Light yellow crystalline. MS: 521 (M−H)⁻.

Example 168 (1RS,2RS)-cyclopropane-1,1,2-tricarboxylic acid2-[(4-chloro-phenyl)-amide]1-(ethyl-methyl-amide)1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1RS,2RS)-2-(4-chloro-phenylcarbamoyl)-1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 165) and ethylmethylamine hydrochloride was prepared(1RS,2RS)-cyclopropane-1,1,2-tricarboxylic acid2-[(4-chloro-phenyl)-amide]1-(ethyl-methyl-amide)1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}. Light yellowcrystalline. MS: 509 (M−H)⁻.

Example 169 (1SR,2RS)-cyclopropane-1,1,2-tricarboxylic acid 1-amide2-[(4-chloro-phenyl)-amide]1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1RS,2RS)-2-(4-chloro-phenylcarbamoyl)-1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 165) and ammonium chloride was prepared(1SR,2RS)-cyclopropane-1,1,2-tricarboxylic acid 1-amide2-[(4-chloro-phenyl)-amide]1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.White crystalline. MS: 467 (M−H)⁻.

Example 170(1RS,2RS)-1-(morpholine-4-carbonyl)-cyclopropane-1,2-dicarboxylic acid2-[(4-chloro-phenyl)-amide]1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1RS,2RS)-2-(4-chloro-phenylcarbamoyl)-1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 165) and morpholine was prepared(1RS,2RS)-1-(morpholine-4-carbonyl)-cyclopropane-1,2-dicarboxylic acid2-[(4-chloro-phenyl)-amide]1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Light yellow crystalline. MS: 539 (M+H)⁺.

Example 171(1RS,2RS)-2-(4-chloro-phenylcarbamoyl)-1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid methyl ester

In analogy to example 157, step 7, from(1RS,2RS)-2-(4-chloro-phenylcarbamoyl)-1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 165) and iodomethane was prepared(1RS,2RS)-2-(4-chloro-phenylcarbamoyl)-1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid methyl ester. Yellow oil. MS: 482 (M−H)⁻.

Example 172(1RS,2RS)-1-(piperidine-1-carbonyl)-cyclopropane-1,2-dicarboxylic acid2-[(4-chloro-phenyl)-amide]1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 72, from(1RS,2RS)-2-(4-chloro-phenylcarbamoyl)-1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (example 165) and piperidine was prepared(1RS,2RS)-1-(piperidine-1-carbonyl)-cyclopropane-1,2-dicarboxylic acid2-[(4-chloro-phenyl)-amide]1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Light yellow oil. MS: 535 (M−H)⁻.

Example 173 (1SR,2RS)-1-hydroxymethyl-cyclopropane-1,2-dicarboxylic acid2-[(4-chloro-phenyl)-amide]1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 148, from(1RS,2RS)-2-(4-chloro-phenylcarbamoyl)-1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid methyl ester (example 171) and sodium borohydride was prepared(1SR,2RS)-1-hydroxymethyl-cyclopropane-1,2-dicarboxylic acid2-[(4-chloro-phenyl)-amide]1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.White crystalline. MS: 454 (M−H)⁻.

Example 174(1RS,2RS)-1-(4-chloro-phenylcarbamoyl)-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid methyl ester

In analogy to example 165, step 3, from(1RS,2RS)-1-(4-chloro-phenylcarbamoyl)-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid(1RS,2RS)-1-(4-chloro-phenylcarbamoyl)-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid that in analogy to example 157, step 7 was methylated to(1RS,2RS)-1-(4-chloro-phenylcarbamoyl)-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid methyl ester. Light yellow oil. MS: 482 (M−H)⁻.

Example 175 (1SR,2RS)-cyclopropane-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(3-oxo-morpholin-4-yl)-phenyl]-amide}

Step 1:

In analogy to example 114, step 5, from3-oxa-bicyclo[3.1.0]hexane-2,4-dione (purchased from ACROS, cat-No:37012-0010) and 4-(4-amino-3-fluoro-phenyl)-morpholin-3-one (preparedaccording to C. F. Bigge et al., patent application WO 2003045912) was(1SR,2RS)3-[2-fluoro-4-(3-oxo-morpholin-4-yl)-phenyl]-3-aza-bicyclo[3.1.0]hexane-2,4-dione.Off-white solid. MS: 321 (M−H)⁻.

Step 2:

In analogy to example 114, step 6. from (1SR,2RS)3-[2-Fluoro-4-(3-oxo-morpholin-4-yl)-phenyl]-3-aza-bicyclo[3.1.0]hexane-2,4-dioneand 2-amino-5-chloropyridine was prepared(1SR,2RS)-cyclopropane-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(3-oxo-morpholin-4-yl)-phenyl]-amide}.White solid. MS: 433 (M+H)⁺.

Example 176(1SR,2SR,3RS)-2-(4-chloro-phenylcarbamoyl)-3-[4-(2-oxo-2H-pyridin-1-yl)-phenyl-carbamoyl]-cyclopropanecarboxylicacid ethyl ester

In analogy to example 68, step 4, from1-(4-amino-phenyl)-1H-pyridin-2-one (prepared according to C. F. Biggeet al., patent application WO 2003045912) and (1RS, 5SR,6RS)-3-(4-chloro-phenyl)-2,4-dioxo-3-aza-bicyclo[3.1.01]hexane-6-carboxylicacid ethyl ester was prepared(1SR,2SR,3RS)-2-(4-chloro-phenylcarbamoyl)-3-[4-(2-oxo-2H-pyridin-1-yl)-phenyl-carbamoyl]-cyclopropanecarboxylicacid ethyl ester. Light brown amorphous solid. MS: 480 (M+H)⁺.

Example 177(1SR,2SR,3RS)-2-(4-chloro-phenylcarbamoyl)-3-[4-(2-oxo-2H-pyridin-1-yl)-phenyl-carbamoyl]-cyclopropanecarboxylicacid

In analogy to example 69, from(1SR,2SR,3RS)-2-(4-chloro-phenylcarbamoyl)-3-[4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid ethyl ester was prepared(1SR,2SR,3RS)-2-(4-chloro-phenylcarbamoyl)-3-[4-(2-oxo-2H-pyridin-1-yl)-phenyl-carbamoyl]-cyclopropanecarboxylicacid. Off-white solid. MS: 450 (M−H)⁻.

Example 178 (1SR,2RS)-1-methyl-cyclopropane-1,2-dicarboxylic acid2-[(5-chloro-pyridin-2-yl)-amide]1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenyl]-amide}

Step 1:

A mixture of 1-methyl-1,2-cyclopropanedicarboxylic acid (0.4 g; CAS82235-80-1) in trifluoroacetic anhydride (5 ml) was stirred under anargon atmosphere for 2 hrs at r.t. The clear solution was concentratedat 0° C. to leave the intermediate anhydride as colorless oil. Thisresidue was dissolved in THF (5 ml), cooled to 0° C. and treated with2-amino-5-chloropyridine (0.5 g). Stirring was continued over night atr.t. whereby the suspension turned into a slightly yellow solution, theninto a white slurry. The reaction mixture was concentrated. The crudeproduct was purified by column chromatography (silica gel; gradient:CH₂Cl₂->CH₂Cl₂/MeOH 9:1) to give(1SR,2RS)-2-(5-chloro-pyridin-2-ylcarbamoyl)-1-methyl-cyclopropane-carboxylicacid (182 mg) as white solid. MS 253.1 ([M−H]⁻).

Step 2:

A suspension of(1SR,2RS)-2-(5-chloro-pyridin-2-ylcarbamoyl)-1-methyl-cyclopropane-carboxylicacid (176 mg) in MeOH (5 ml) was cooled to 0° C. and treated withthionyl chloride (15 drops). After stirring for 2 hrs at 0° C.additional thionyl chloride (10 drops) was added. The clear solution wasconcentrated. The crude product was purified by column chromatography(silica gel; gradient: CH₂Cl₂->CH₂Cl₂/MeOH 9:1) to give(1SR,2RS)-2-(5-chloro-pyridin-2-ylcarbamoyl)-1-methyl-cyclopropanecarboxylicacid methyl ester (163 mg) as colorless amorphous solid. MS 269.5([M+H]⁺).

Step 3:

A suspension of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (447 mg;CAS 536747-52-1, prepared according to C. F. Bigge et al., patentapplication WO 2003045912) in dioxane (8 ml) was treated with trimethylaluminium (2M in heptane; 1.09 ml) at r.t. under an argon atmosphere.After stirring for 2 hrs at r.t.,(1SR,2RS)-2-(5-chloro-pyridin-2-ylcarbamoyl)-1-methyl-cyclo-propanecarboxylicacid methyl ester (147 mg) was added. The reaction was heated over nightat 100° C. The slurry was cooled to r.t. and treated with H₂O (0.8 ml).After stirring for 15 min, Na₂SO₄ was added. After stirring for 15 min,the mixture was filtered, and the filtrate was concentrated. The crudeproduct was purified by column chromatography (silica gel; gradient:CH₂Cl₂->CH₂Cl₂/MeOH) to give(1SR,2RS)-1-methyl-cyclopropane-1,2-dicarboxylic acid2-[(5-chloro-pyridin-2-yl)-amide]1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenyl]-amide}(180 mg) as off-white solid. MS: 441.3 ([M+H]⁺)

Example 179 (1S,2R)-1-methyl-cyclopropane-1,2-dicarboxylic acid2-[(5-chloro-pyridin-2-yl)-amide]1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenyl]-amide}and (1R,2S)-1-methyl-cyclopropane-1,2-dicarboxylic acid2-[(5-chloro-pyridin-2-yl)-amide]1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenyl]-amide}

(1SR,2RS)-1-Methyl-cyclopropane-1,2-dicarboxylic acid2-[(5-chloro-pyridin-2-yl)-amide]1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(example 178.3) was separated into its enantiomers using HPLC on achiral stationary phase (Chiralcel OD) using 20% EtOH in heptane aseluent to give (1S,2R)-1-methyl-cyclopropane-1,2-dicarboxylic acid2-[(5-chloro-pyridin-2-yl)-amide]1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenyl]-amide}and (1R,2S)-1-methyl-cyclopropane-1,2-dicarboxylic acid2-[(5-chloro-pyridin-2-yl)-amide]1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenyl]-amide},both as off-white solids.

Example 180 (1SR,2RS)-1-methyl-cyclopropane-1,2-dicarboxylic acid2-[(5-chloro-pyridin-2-yl)-amide]1-{[4-(3-oxo-morpholin-4-yl)-phenyl]-amide}

In analogy to example 178, step 3,(1SR,2RS)-2-(5-chloro-pyridin-2-ylcarbamoyl)-1-methyl-cyclopropanecarboxylicacid methyl ester (example 178, step 2) was reacted with4-(4-amino-phenyl)-morpholin-3-one (CAS 438056-69-0) to give(1SR,2RS)-1-methyl-cyclopropane-1,2-dicarboxylic acid2-[(5-chloro-pyridin-2-yl)-amide]1-{[4-(3-oxo-morpholin-4-yl)-phenyl]-amide}as light yellow solid. MS 427.4 ([M−H]⁻).

Example 181 (1SR,2RS)-1-methyl-cyclopropane-1,2-dicarboxylic acid2-[(5-chloro-pyridin-2-yl)-amide]1-{[2-fluoro-4-(2-oxo-pyrazin-1-yl)-phenyl]-amide}

In analogy to example 178, step 3,(1SR,2RS)-2-(5-chloro-pyridin-2-ylcarbamoyl)-1-methyl-cyclopropanecarboxylicacid methyl ester (example 178, step 2) was reacted with1-(4-amino-3-fluoro-phenyl)-1H-pyrazin-2-one (prepared from2-fluoro-4-iodoaniline by reaction with 1H-pyrazin-2-one, Cu(I) I,N,N′-dimethylethylenediamine and cesium carbonate in dioxane at 120° C.)to give (1SR,2RS)-1-methyl-cyclopropane-1,2-dicarboxylic acid2-[(5-chloro-pyridin-2-yl)-amide]1-{[2-fluoro-4-(2-oxo-pyrazin-1-yl)-phenyl]-amide}as off-white solid. MS 440.3 ([M−H]⁻).

Example 182 (1SR,2RS)-1-methyl-cyclopropane-1,2-dicarboxylic acid2-[(5-chloro-pyridin-2-yl)-amide]1-{[4-(2-oxo-pyridin-1-yl)-phenyl]-amide}

In analogy to example 178, step 3,(1SR,2RS)-2-(5-chloro-pyridin-2-ylcarbamoyl)-1-methyl-cyclopropanecarboxylicacid methyl ester (example 178, step 2) was reacted with1-(4-amino-phenyl)-1H-pyridin-2-one (CAS 13143-47-0) to give(1SR,2RS)-1-methyl-cyclopropane-1,2-dicarboxylic acid2-[(5-chloro-pyridin-2-yl)-amide]1-{[4-(2-oxo-pyridin-1-yl)-phenyl]-amide}as off-white solid. MS 421.1 ([M−H]⁻)

Example 183 (1SR,2RS)-1-methyl-cyclopropane-1,2-dicarboxylic acid2-[(5-chloro-pyridin-2-yl)-amide]1-{[2-fluoro-4-(3-oxo-morpholin-4-yl)-phenyl]-amide}

In analogy to example 178, step 3,(1SR,2RS)-2-(5-chloro-pyridin-2-ylcarbamoyl)-1-methyl-cyclopropanecarboxylicacid methyl ester (example 178, step 2) was reacted with4-(4-amino-3-fluoro-phenyl)-morpholin-3-one (CAS 438056-69-0) to give(1SR,2RS)-1-methyl-cyclopropane-1,2-dicarboxylic acid2-[(5-chloro-pyridin-2-yl)-amide]1-{[2-fluoro-4-(3-oxo-morpholin-4-yl)-phenyl]-amide}as yellow solid. MS 445.1 ([M−H])

Example 184 (1SR,2RS)-1-methyl-cyclopropane-1,2-dicarboxylic acid2-[(5-chloro-pyridin-2-yl)-amide]1-{[2-methyl-4-(2-oxo-pyridin-1-yl)-phenyl]-amide}

In analogy to example 178, step 3,(1SR,2RS)-2-(5-chloro-pyridin-2-ylcarbamoyl)-1-methyl-cyclopropanecarboxylicacid methyl ester (example 178, step 2) was reacted with1-(4-amino-3-methyl-phenyl)-1H-pyridin-2-one to give(1SR,2RS)-1-methyl-cyclopropane-1,2-dicarboxylic acid2-[(5-chloro-pyridin-2-yl)-amide]1-{[2-methyl-4-(2-oxo-pyridin-1-yl)-phenyl]-amide}as off-white solid. MS 435.1 ([M−H]⁻)

Example 185 (1SR,2RS)-1-methyl-cyclopropane-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenyl]-amide}

Step 1:

In analogy to example 178, step 1,1-methyl-1,2-cyclopropanedicarboxylicacid (CAS 82235-80-1) was converted into the corresponding anhydride andthen reacted with 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (CAS536747-52-1, prepared according to C. F. Bigge et al., patentapplication WO 2003045912) to give(1SR,2RS)-2-[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-1-methyl-cyclopropanecarboxylicacid. Off-white solid.

Step 2:

In analogy to example 178, step 2,(1SR,2RS)-2-[2-gluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-1-methyl-cyclopropanecarboxylicacid was converted to(1SR,2RS)-2-[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-1-methyl-cyclopropanecarboxylicacid methyl ester. White amorphous solid. 345.4 ([M+H]⁺).

Step 3:

In analogy to example 178, step 3,(1SR,2RS)-2-[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-1-methyl-cyclopropanecarboxylicacid methyl ester was reacted with 2-amino-5-chloro-pyridine to give(1SR,2RS)-1-methyl-cyclopropane-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenyl]-amide}as light yellow amourphous solid. MS 441.3 ([M+H]⁺).

Example 186 (1RS,2SR)-cyclopropane-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

Step 1:

A solution of 3-oxabicyclo[3.1.0]hexane-2,4-dione (160 mg) in THF (5 ml)was treated with 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (321 mg;CAS 536747-52-1, prepared according to C. F. Bigge et al., patentapplication WO 2003045912). The suspension was stirred over night atr.t. The solid was collected by filtration, triturated with 1N HCl (5ml), again collected by filtration, washed with 1N HCl, H₂O, thencyclohexane and dried to give(1RS,2SR)-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (144 mg) as off-white solid. MS: 315.3 ([M−H]⁻)

Step 2:

A stirred suspension of(1RS,2SR)-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid (140 mg) in MeOH (5 ml) was cooled to 0° C. and treated withthionyl chloride (10 drops). The mixture turned immediately into a clearsolution. Stirring was continued for 3 hrs at 0° C. Then the reactionmixture was concentrated. The crude product was purified by columnchromatography (silica gel; gradient: CH₂Cl₂->CH₂Cl₂/MeOH) to give(1RS,2SR)-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid methyl ester (84 mg) as colorless amorphous solid. MS: 353.4([M+H]⁺).

Step 3:

A solution of 2-amino-5-chloropyridine (125 mg) in dioxane (4 ml) wastreated with trimethyl aluminium (2M in heptane; 0.48 ml) at r.t. underan argon atmosphere. After stirring for 1 hr at r.t.,(1RS,2SR)-2-[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid methyl ester (80 mg) in dioxane (1 ml) was added. The reaction washeated over night at 90° C., then cooled to r.t. and treated with H₂O(0.6 ml). After stirring for 15 min, Na₂SO₄ was added. After stirringfor 15 min, the mixture was diluted with CH₂Cl₂ and filtered. Thefiltrate was concentrated. The crude product was purified by columnchromatography (silica gel; gradient: CH₂Cl₂->CH₂Cl₂/MeOH) to give(1RS,2SR)-cyclopropane-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(85 mg) as light yellow solid. MS: 427.4 ([M+H]⁺).

Example 187 (1RS,2SR)-cyclopropane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 186, step 2,(1RS,2SR)-2-[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylicacid methyl ester (example 1.2) was reacted with 4-chloroaniline to give(1RS,2SR)-cyclopropane-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}as off-white solid. MS: 426.0 ([M+H]⁺).

Example 188 (1S,2R,3R)-3-hydroxymethyl-cyclopropane-1,2-dicarboxylicacid1-[(5-chloro-pyridin-2-yl)-amide]2-[{2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

In analogy to example 132, step 2, from(1S,2R,3R)-3-(4-methoxy-benzyloxymethyl)-cyclopropane-1,2-dicarboxylicacid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(example 157) was prepared(1S,2R,3R)-3-hydroxymethyl-cyclopropane-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}.Colorless solid. MS: 455 (M−H)⁻.

Example A

Film coated tablets containing the following ingredients can bemanufactured in a conventional manner:

Ingredients Per tablet Kernel: Compound of formula (I) 10.0 mg 200.0 mgMicrocrystalline cellulose 23.5 mg 43.5 mg Lactose hydrous 60.0 mg 70.0mg Povidone K30 12.5 mg 15.0 mg Sodium starch glycolate 12.5 mg 17.0 mgMagnesium stearate 1.5 mg 4.5 mg (Kernel Weight) 120.0 mg 350.0 mg FilmCoat: Hydroxypropyl methyl cellulose 3.5 mg 7.0 mg Polyethylene glycol6000 0.8 mg 1.6 mg Talc 1.3 mg 2.6 mg Iron oxyde (yellow) 0.8 mg 1.6 mgTitan dioxide 0.8 mg 1.6 mg

The active ingredient is sieved and mixed with microcristallinecellulose and the mixture is granulated with a solution ofpolyvinylpyrrolidon in water. The granulate is mixed with sodium starchglycolate and magesiumstearate and compressed to yield kernels of 120 or350 mg respectively. The kernels are lacquered with an aqueoussolution/suspension of the above mentioned film coat.

Example B

Capsules containing the following ingredients can be manufactured in aconventional manner:

Ingredients Per capsule Compound of formula (I) 25.0 mg Lactose 150.0 mgMaize starch 20.0 mg Talc 5.0 mg

The components are sieved and mixed and filled into capsules of size 2.

Example C

Injection solutions can have the following composition:

Compound of formula (I) 3.0 mg Polyethylene Glycol 400 150.0 mg AceticAcid q.s. ad pH 5.0 Water for injection solutions ad 1.0 ml

The active ingredient is dissolved in a mixture of Polyethylene Glycol400 and water for injection (part). The pH is adjusted to 5.0 by AceticAcid. The volume is adjusted to 1.0 ml by addition of the residualamount of water. The solution is filtered, filled into vials using anappropriate overage and sterilized.

Example D

Soft gelatin capsules containing the following ingredients can bemanufactured in a conventional manner:

Capsule contents Compound of formula (I) 5.0 mg Yellow wax 8.0 mgHydrogenated Soya bean oil 8.0 mg Partially hydrogenated plant oils 34.0mg Soya bean oil 110.00 mg Weight of capsule contents 165.0 mg

Gelatin capsule Gelatin 75.0 mg Glycerol 85% 32.0 mg Karion 83 8.0 mg(dry matter) Titan dioxide 0.4 mg Iron oxide yellow 1.1 mg

The active ingredient is dissolved in a warm melting of the otheringredients and the mixture is filled into soft gelatin capsules ofappropriate size. The filled soft gelatin capsules are treated accordingto the usual procedures.

Example E

Sachets containing the following ingredients can be manufactured in aconventional manner:

Compound of formula (I) 50.0 mg Lactose, fine powder 1015.0 mgMicrocristalline cellulose (AVICEL PH 102) 1400.0 mg Sodiumcarboxymethyl cellulose 14.0 mg Polyvinylpyrrolidon K 30 10.0 mgMagnesiumstearate 10.0 mg Flavoring additives 1.0 mg

The active ingredient is mixed with lactose, microcristalline celluloseand sodium carboxymethyl cellulose and granulated with a mixture ofpolyvinylpyrrolidon in water. The granulate is mixed withmagnesiumstearate and the flavouring additives and filled into sachets.

Example F

Factor Xa activity was measured spectrophotometrically in microtiterplates in a final volume of 150 μl using the following conditions:Inhibition of human factor Xa (Enzyme Research Laboratories) was testedat an enzyme concentration of 3 nM using the chromogenic substrateS-2222 (Chromogenix AB, Molndal, Sweden) at 200 nM. The reactionkinetics of the enzyme and the substrate were linear with both time andthe enzyme concentration. The inhibitors were dissolved in DMSO andtested at various concentrations up to 100 μM. The inhibitors werediluted using HNPT buffer consisting of HEPES 100 mM, NaCl 140 mM, PEG6000 0.1% and Tween 80 0.02%, pH 7.8. The cleavage of S-2222 by humanfactor Xa was followed at 405 nm for 5 minutes at room temperature. Thevelocity of the reaction was determined by the autoreader from the slopeof the linear regression fit to 7 time points (1 minute). The initialvelocity for each inhibitor concentration was determined by the slope ofat least 4 time points in the linear phase by a linear regression fit(mOD/min²). Apparent dissociation constants K_(i) were calculatedaccording to Cheng and Prusoff [Cheng, Y. C.; Prusoff, W. H.Relationship between the inhibition constant (K_(i)) and theconcentration of the inhibitor that causes 50 percent inhibition (IC₅₀)of an enzyme reaction. Biochem. Pharmacol. 1973, 22, 3099-3108.] basedon the IC₅₀ and the respective K_(m), determined previously(K_(i)=IC₅₀/(1+S/K_(m))). The K_(m) for the substrate used wasdetermined under the conditions of the test with at least 5 substrateconcentrations ranging from 0.5 to 15 times K_(m). [Lottenberg R, Hall JA, Blinder M, Binder E P, Jackson C M., The action of thrombin onpeptide p-nitroanilide substrates. Substrate selectivity and examinationof hydrolysis under different reaction conditions. Biochim Biophys Acta.1983 Feb. 15; 742(3):539-57]. according to Eadie [Eadie G. S. Theinhibition of cholinesterase by physostigmine and prostigmine. J. Biol.Chem. 1942, 146, 85-93.]. The K_(m) for S-2222 amounted to 613 μM.

Ki [μM] Example factor Xa 47 0.009 48 0.008 52 0.013

1. A compound of formula (I)

wherein A is —CONH— or —NHCO—; B is optionally substituted phenyl,optionally substituted heteroaryl or optionally substitutedheterocyclyl; R^(c) is optionally substituted aryl, optionallysubstituted heteroaryl or optionally substituted heterocyclyl, one ortwo carbon atoms of said aryl, heteroaryl or heterocyclyl ringoptionally being replaced with a carbonyl group; D is aryl optionallysubstituted by one, two or three halogen atoms independently selectedfrom chlorine, fluorine and bromine or heteroaryl optionally substitutedby one, two or three halogen atoms independently selected from chlorine,fluorine and bromine; E is E-3:

R⁷, R⁸, R⁹ and R¹⁰ are independently from each other hydrogen, C₁₋₆alkyl or hydroxy.
 2. A compound according to claim 1, wherein D is aryloptionally substituted by one halogen atom selected from chlorine andbromine or heteroaryl optionally substituted by one halogen atomselected from chlorine and bromine.
 3. A compound according to claim 1,wherein D is phenyl, pyridyl, thienyl, pyrimidinyl, pyridazinyl orindolyl, said phenyl, pyridyl, thienyl, pyrimidinyl, pyridazinyl orindolyl being optionally substituted by one halogen atom selected fromchlorine and bromine.
 4. A compound according to claim 1, wherein D ischlorophenyl or chloropyridyl.
 5. A compound according to claim 1,wherein B is optionally substituted phenyl or optionally substitutedheteroaryl.
 6. A compound according to claim 1, wherein B is phenyl orpyridyl, said phenyl or pyridyl being optionally substituted by one ortwo halogen atoms selected independently from the group consisting ofchlorine, fluorine and bromine.
 7. A compound according to claim 1,wherein B is phenyl substituted by one or two fluorine.
 8. A compoundaccording to claim 1, wherein B is fluorophenyl.
 9. A compound accordingto claim 1, wherein B is 2-fluorophenyl.
 10. A compound according toclaim 1, wherein R^(c) is aryl, heteroaryl or heterocyclyl, one carbonatom of said aryl, heteroaryl or heterocyclyl ring optionally beingreplaced with a carbonyl group, and said aryl, heteroaryl orheterocyclyl ring optionally being substituted by hydroxy, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ alkyl sulfonyl, amino C₁₋₆ alkyl, mono-C₁₋₆ alkylsubstituted amino-C₁₋₆ alkyl or di-C₁₋₆ alkyl substituted amino-C₁₋₆alkyl.
 11. A compound according to claim 1, wherein R^(c) is aryl,heteroaryl or heterocyclyl, one carbon atom of said aryl, heteroaryl orheterocyclyl ring being replaced with a carbonyl group at ortho positionwith respect to B, and said aryl, heteroaryl or heterocyclyl ringoptionally being substituted by hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆alkyl sulfonyl, amino C₁₋₆ alkyl, mono-C₁₋₆ alkyl substituted amino-C₁₋₆alkyl or di-C₁₋₆ alkyl substituted amino-C₁₋₆ alkyl.
 12. A compoundaccording to claim 1, wherein R^(c) is 2-oxo-2H-pyridin-1-yl optionallysubstituted by C₁₋₆ alkyl or C₁₋₆ alkoxy.
 13. A compound according toclaim 1, wherein —B—R^(c) is 2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl.14. A compound according to claim 1, wherein A is —CONH—.
 15. Apharmaceutical composition comprising a compound according to claim 1and a pharmaceutically acceptable excipient.